Salts of quinazoline derivative or crystals thereof, and the process for producing thereof

ABSTRACT

Crystals of a quinazoline derivative are provided. The present invention relates to an acid addition salt of a compound represented by Formula (I): 
                         
a pharmaceutical composition containing it, and the like.

TECHNICAL FIELD

The present invention relates to an acid addition salt or crystals ofthe acid addition salt of a quinazoline derivative, and a pharmaceuticalcomposition containing them. Moreover, the present invention relates tomethods for producing the acid addition salt, the crystals of the acidaddition salt, and the pharmaceutical composition containing them.

BACKGROUND ART

Tyrosine kinase is an enzyme which phosphorylates tyrosine residues insubstrate proteins, and is known to play an important role in anintracellular signal transduction system concerning cellulardifferentiation and proliferation. Especially, it is known that a growthfactor receptor tyrosine kinase (hereinafter receptor tyrosine kinase)such as HER2 (also called as ErbB2 or Neu) and EGF receptor etc. areconsiderably involved in cancer development, and their activities areincreased in a variety of human cancers (Non-Patent Document 1,Non-Patent Document 2 and Non-Patent Document 3).

Also it is known that co-expression of EGF receptor and HER2 furtherpromotes canceration by EGF receptor alone (Non-Patent Document 4) and adual inhibitor that inhibits tyrosine kinase of both EGF receptor andHER2 is advantageous in having superior therapeutic effect in widerrange of disease by synergistic effect of dual inhibition when comparedwith a EGF receptor or a HER2 selective inhibitor.

According to Patent Document 1, a quinazoline derivative represented bythe following Formula:

has dual inhibitory activity for EGF receptor and HER2, and is useful asa therapeutic and/or prophylactic agent for cancer. The followingcompound (VIII-102):

in a free base form is disclosed in an Example thereof, but neither anacid addition salt nor a solvate thereof is specifically disclosed.Also, crystals thereof are not specifically disclosed.

A method for producing a quinazoline derivative represented by Formula(VI′):

is described in Patent Document 2. Also, the following compound (VI-15):

in a free base form is disclosed in an Example thereof, but neither anacid addition salt nor a solvate thereof is specifically disclosed.Also, crystals thereof are not specifically disclosed.

Patent Documents 3 and 4 disclose hydrate crystals and anhydridecrystals of Lapatinib ditosylate (ditosylate salt ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine)that has a dual inhibitory action for EGF receptor and HER2, and isrepresented by the following Formula.

Also, Patent Document 5 discloses anhydride crystals of a free base ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine.

In drug delivery, a crystal form that has useful and excellent chemicaland/or physical properties is desired.

PRIOR ART REFERENCES Patent Document

-   [Patent Document 1] International Publication No. WO 2006/090717-   [Patent Document 2] International Publication No. WO 2010/074150-   [Patent Document 31] International Publication No. WO 2002/002552-   [Patent Document 4] International Publication No. WO 2009/079541-   [Patent Document 5] International Publication No. WO 2009/079547

Non-Patent Document

-   [Non-patent Document 1] Cancer Research (Cancer Res.), 1991, vol.    51, p. 4430-4435-   [Non-patent Document 2] Cancer Research (Cancer Res.), 1992, vol.    52, p. 3636-3641-   [Non-patent Document 3] Cancer Chemotherapy and Pharmacology (Cancer    Chemother. Pharmacol.), 1993, vol. 32, p. 1-19-   [Non-patent Document 4] Cell, 1989, vol. 58, p. 287-292

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

Active pharmaceutical ingredients may have substantially differentphysical properties according to the respective solid forms. Suchdifferences in physical properties may influence, for example, aproduction method or an administration method for an activepharmaceutical ingredient or influence a pharmaceutical compositioncontaining an active pharmaceutical ingredient. The present inventionprovides an acid addition salt or a solvate thereof of a compoundrepresented by Formula (I) or their crystals more useful in a productionmethod or an administration method for an active pharmaceuticalingredient or a pharmaceutical composition containing an activepharmaceutical ingredient than the other solid forms. Moreover, thepresent invention provides an intermediate useful for producing the acidaddition salt, the solvate thereof, or their crystals.

Although the compound represented by Formula (I) is already disclosed,it is desired to establish a suitable solid form and a more preferableproduction method for using the compound as a pharmaceutical product orfor industrially producing the compound as a pharmaceutical product.

Means for Solving the Problem

As a result of having conducted diligent research, the inventors havefound that in hydrochloride of the compound represented by Formula (I),there are crystal forms of Form I, Form II, Form III, Form V, Form VIand Form VII of monohydrochloride and crystal form of ethanolate ofmonohydrochloride. Also, the inventors have found that there are crystalforms of mono-p-toluenesulfonate; monosulfate and monosulfate hydrate;monophosphate and monophosphate hydrate; and monofumarate of thecompound represented by Formula (I). Furthermore, the inventors havefound that crystal forms of Form I, Form V and Form VI ofmonohydrochloride as well as crystal form of mono-p-toluenesulfonate aremore thermodynamically stable than other crystal forms.

Also, the inventors have found a compound represented by Formula (II), apharmaceutically acceptable salt thereof, their solvates, or theircrystals useful for producing hydrochloride or crystals of thehydrochloride, or mono-p-toluenesulfonate or crystals of themono-p-toluenesulfonate of the compound represented by Formula (I)useful as an active pharmaceutical ingredient.

The present invention relates to the following items 1) to 36).

1) Hydrochloride of a compound represented by Formula (I):

or a solvate thereof.

2) The hydrochloride or solvate thereof according to the above item 1),wherein the hydrochloride is monohydrochloride.

3) A crystal of hydrochloride of a compound represented by Formula (I).

4) The crystal according to the above item 3), wherein the hydrochlorideis monohydrochloride.

5) The crystal according to the above item 4), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:8.0-0.2°, 14.1°±0.2°, 20.6°±0.2°, 21.0°±0.2°, and 25.8°±0.2°.

6) The crystal according to the above item 4), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:6.8°±0.2°, 8.0°±0.2°, 14.1°±0.2°, 17.9°±0.2°, 18.5°±0.2°, 20.6°±0.2°,21.0°±0.2°, 22.5°±0.2°, 25.8°±0.2°, and 28.4°±0.2°.

7) The crystal according to the above item 4), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:23.9°±0.2°, 25.9°±0.2°, 26.2°±0.2°, 26.7°±0.2°, and 28.4°±0.2°.

8) The crystal according to the above item 4), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:7.9°±0.2°, 9.7°±0.2°, 11.9°±0.2°, 15.8°±0.2°, 18.5°±0.2°, 23.9°±0.2°,25.9°±0.2°, 26.2°±0.2°, 26.7°±0.2°, and 28.4°±0.2°.

9) The crystal according to the above item 4), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:5.4°±0.2°, 16.3°±0.2°, 21.6°±0.2°, 23.2°±0.2°, and 23.7°±0.2°.

10) The crystal according to the above item 4), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:5.4°±0.2°, 8.9°±0.2°, 11.7°±0.2°, 13.8°±0.2°, 16.3°±0.2°, 20.9°±0.2°,21.6°±0.2°, 23.2°±0.2°, 23.7°±0.2°, and 26.6°±0.2°.

11) A pharmaceutical composition comprising the hydrochloride or solvatethereof according to the above item 1) or 2).

11′) A pharmaceutical composition comprising the crystal according toany one of the above items 3) to 10).

12) The pharmaceutical composition according to the above item 11) foruse in treatment and/or prophylaxis of cancer.

12′) The pharmaceutical composition according to the above item 12),wherein the cancer is breast cancer.

12″) The pharmaceutical composition according to the above item 11),having EGF receptor inhibitory activity and HER2 inhibitory activity.

13) A treatment and/or prophylactic agent for cancer, comprising thecrystal according to any one of the above items 3) to 10).

14) A method for treating and/or preventing cancer, comprisingadministering a pharmaceutical composition comprising the crystalaccording to any one of the above items 3) to 10).

15) Use of the crystal according to any one of the above items 3) to 10)for producing a medicament for treatment and/or prophylaxis of cancer.

16) The crystal according to any one of the above items 3) to 10) fortreatment and/or prophylaxis of cancer.

17) A pharmaceutical composition for oral administration comprising thecrystal according to any one of the above items 3) to 10).

18) The pharmaceutical composition according to the above item 17),which is a tablet, powder, granule, capsule, pill, film, suspension,emulsion, elixir, syrup, lemonade, spirit, aromatic water, extract,decoction, or tincture.

19) The pharmaceutical composition according to the above item 18),which is a sugar-coated tablet, film-coated tablet, enteric-coatedtablet, sustained-release tablet, troche tablet, sublingual tablet,buccal tablet, chewable tablet, orally disintegrating tablet, dry syrup,soft capsule, microcapsule, or sustained-release capsule.

20) A pharmaceutical composition for parenteral administrationcomprising the crystal according to any one of the above items 3) to10).

21) The pharmaceutical composition according to the above item 20), fordermal, subcutaneous, intravenous, intraarterial, intramuscular,intraperitoneal, transmucosal, inhalation, transnasal, ophthalmic, innerear, or vaginal administration.

22) The pharmaceutical composition according to the above item 20) or21), which is an injection, infusion, eye drop, nose drop, ear drop,aerosol, inhalation, lotion, impregnation, liniment, mouthwash, enema,ointment, plaster, jelly, cream, patch, cataplasm, external powder, orsuppository.

23) A pharmaceutical composition for a pediatric or geriatric patientcomprising the crystal according to any one of the above items 3) to10).

24) The crystal according to the above item 4), characterized by X-raypowder diffraction spectrum substantially in accordance with FIG. 1.

25) The crystal according to the above item 4), characterized by X-raypowder diffraction spectrum substantially in accordance with FIG. 2.

26) The crystal according to the above item 4), characterized by X-raypowder diffraction spectrum substantially in accordance with FIG. 3.

27) A compound represented by Formula (II):

or a pharmaceutically acceptable salt, or solvate thereof.

28) The salt or solvate thereof according to the above item 27), whereinthe salt is di-p-toluene sulfonate.

29) A crystal of di-p-toluenesulfonate of a compound represented byFormula (II).

30) The crystal according to the above item 29), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:6.4°±0.2°, 7.3°±0.2°, 21.1°±0.2°, 24.7°±0.20, and 25.3°±0.2°.

31) The crystal according to the above item 29), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:6.4°±0.2°, 7.3°±0.2°, 11.4°±0.2°, 15.2°±0.2°, 17.6°±0.2°, 20.1°±0.2°,21.1°±0.2°, 21.7°±0.2°, 24.7°±0.2°, and 25.3°±0.2°.

32) A crystal of di-p-toluenesulfonate dihydrate of a compoundrepresented by Formula (II).

33) The crystal according to the above item 32), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:7.3°±0.2°, 17.0°±0.2°, 18.5°±0.2°, 22.6°±0.2°, and 24.0°±0.2°.

34) The crystal according to the above item 32), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:7.3°±0.2°, 17.0°±0.2°, 18.5°±0.2°, 19.7°±0.2°, 21.7°±0.2°, 22.6°±0.2°,22.8°±0.2°, 24.0°±0.2°, 24.8°±0.2°, and 29.7°±0.2°.

35) The crystal according to the above item 29), characterized by X-raypowder diffraction spectrum substantially in accordance with FIG. 10.

36) The crystal according to the above item 32), characterized by X-raypowder diffraction spectrum substantially in accordance with FIG. 11.

Moreover, the present invention relates to the following items 1A) to105A).

1A) A salt of a compound represented by Formula (I)

or a solvate thereof.

2A) The salt or solvate thereof according to the above item 1A), whereinthe salt is hydrochloride.

3A) The salt or solvate thereof according to the above item 1A) or 2A),wherein the salt is monohydrochloride.

4A) A crystal of hydrochloride of a compound represented by Formula (I).

5A) The crystal according to the above item 4A), wherein thehydrochloride is monohydrochloride.

6A) The crystal according to the above item 5A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:8.0°±0.2°, 14.1°±0.2°, 20.6°±0.2°, 21.0°±0.2°, and 25.8°±0.2°.

7A) The crystal according to the above item 5A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:6.8°±0.2°, 8.0°±0.2°, 14.1°±0.2°, 17.9±0.2°, 18.5°±0.2°, 20.6°±0.2°,21.0°±0.2°, 22.5°±0.2°, 25.8°±0.2°, and 28.4°±0.2°.

8A) The crystal according to the above item 5A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:23.9°±0.2°, 25.9°±0.2°, 26.2°±0.2°, 26.7°±0.2°, and 28.4°±0.2°.

9A) The crystal according to the above item 5A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:7.9°±0.2°, 9.7°±0.2°, 11.9°±0.2°, 15.8°±0.2°, 18.5°±0.2°, 23.9°±0.2°,25.9°±0.2°, 26.2°±0.2°, 26.7°±0.2°, and 28.4°±0.2°.

10A) The crystal according to the above item 5A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:5.4°±0.2°, 16.3°±0.2°, 21.6°±0.2°, 23.2°±0.2°, and 23.7°±0.2°.

11A) The crystal according to the above item 5A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:5.4°±0.2°, 8.9°±0.2°, 11.7°±0.2°, 13.8°±0.2°, 16.3°±0.2°, 20.9°±0.2°,21.6°±0.2°, 23.2°±0.2°, 23.7°±0.2°, and 26.6°±0.2°.

12A) A pharmaceutical composition comprising the hydrochloride orsolvate thereof according to the above item 2A) or 3A).

13A) A pharmaceutical composition comprising the crystal according toany one of the above items 4A) to 11A).

13A′) A pharmaceutical composition comprising the crystal according toany one of the above items 4A) to 11A), wherein an amount of an impurityis 2% by weight or less.

13A″) The pharmaceutical composition according to the above item 13A′),wherein the impurity is an E isomer of the compound represented byFormula (I).

14A) The salt or solvate thereof according to the above item 1A),wherein the salt is p-toluenesulfonate.

15A) The salt or solvate thereof according to the above item 1A) or14A), wherein the salt is mono-p-toluenesulfonate.

16A) A crystal of p-toluenesulfonate of a compound represented byFormula (I).

17A) The crystal according to the above item 16A), wherein thep-toluenesulfonate is mono-p-toluenesulfonate.

18A) The crystal according to the above item 17A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:13.7°±0.2°, 15.7°±0.2°, 20.0°±0.2°, 22.7°±0.2°, and 25.3°±0.2°.

19A) The crystal according to the above item 17A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:6.1°±0.2°, 6.4°±0.2°, 10.8°±0.2°, 13.7°±0.2°, 15.7°±0.2°, 16.3°±0.2°,20.0°±0.2°, 22.7°±0.2°, 24.6°±0.2°, and 25.3°±0.2°.

20A) A pharmaceutical composition comprising the p-toluenesulfonate orsolvate thereof according to the above item 14A) or 15A).

21A) A pharmaceutical composition comprising the crystal according toany one of the above items 16A) to 19A).

21A′) A pharmaceutical composition comprising the crystal according toany one of the above items 16A) to 19A), wherein an amount of animpurity is 2% by weight or less.

21A″) The pharmaceutical composition according to the above item 21A′),wherein the impurity is an E isomer of the compound represented byFormula (I).

22A) The pharmaceutical composition according to the above item 12A) or20A) for use in treatment and/or prophylaxis of cancer.

23A) The pharmaceutical composition according to the above item 13A) or21A) for use in treatment and/or prophylaxis of cancer.

24A) The pharmaceutical composition according to the above item 22A),wherein the cancer is breast cancer.

25A) The pharmaceutical composition according to the above item 23A),wherein the cancer is breast cancer.

26A) The pharmaceutical composition according to the above item 12A) or20A), having EGF receptor inhibitory activity and HER2 inhibitoryactivity.

27A) The pharmaceutical composition according to the above item 13A) or21A), having EGF receptor inhibitory activity and HER2 inhibitoryactivity.

28A) A treatment and/or prophylactic agent for cancer, comprising thecrystal according to any one of the above items 4A) to 11A).

29A) A treatment and/or prophylactic agent for cancer, comprising thecrystal according to any one of the above items 16A) to 19A).

30A) A method for treating and/or preventing cancer, comprisingadministering a pharmaceutical composition comprising the crystalaccording to any one of the above items 4A) to 11A).

30A′) The method for treating and/or preventing cancer according to theabove item 30A), wherein the cancer is breast cancer.

31A) A method for treating and/or preventing cancer, comprisingadministering a pharmaceutical composition comprising the crystalaccording to any one of the above items 16A) to 19A).

31A′) The method for treating and/or preventing cancer according to theabove item 31A), wherein the cancer is breast cancer.

32A) Use of the crystal according to any one of the above items 4A) to11A) for producing a medicament for treatment and/or prophylaxis ofcancer.

32A′) The use of the crystal according to the above item 32A), whereinthe cancer is breast cancer.

33A) Use of the crystal according to any one of the above items 1 GA) to19A) for producing a medicament for treatment and/or prophylaxis ofcancer.

33A′) The use of crystal according to the above item 33A), wherein thecancer is breast cancer.

34A) The crystal according to any one of the above items 4A) to 11A) fortreatment and/or prophylaxis of cancer.

34A′) The crystal according to the above item 34A), wherein the canceris breast cancer.

35A) The crystal according to any one of the above items 16A) to 19A)for treatment and/or prophylaxis of cancer.

35A′) The crystal according to the above item 35A), wherein the canceris breast cancer.

36A) A pharmaceutical composition for oral administration comprising thecrystal according to any one of the above items 4A) to 11A).

37A) A pharmaceutical composition for oral administration comprising thecrystal according to any one of the above items 16A) to 19A).

38A) The pharmaceutical composition according to the above item 36A),which is a tablet, powder, granule, capsule, pill, film, suspension,emulsion, elixir, syrup, lemonade, spirit, aromatic water, extract,decoction, or tincture.

39A) The pharmaceutical composition according to the above item 37A),which is a tablet, powder, granule, capsule, pill, film, suspension,emulsion, elixir, syrup, lemonade, spirit, aromatic water, extract,decoction, or tincture.

40A) The pharmaceutical composition according to the above item 38A),which is a sugar-coated tablet, film-coated tablet, enteric-coatedtablet, sustained-release tablet, troche tablet, sublingual tablet,buccal tablet, chewable tablet, orally disintegrating tablet, dry syrup,soft capsule, microcapsule, or sustained-release capsule.

41A) The pharmaceutical composition according to the above item 39A),which is a sugar-coated tablet, film-coated tablet, enteric-coatedtablet, sustained-release tablet, troche tablet, sublingual tablet,buccal tablet, chewable tablet, orally disintegrating tablet, dry syrup,soft capsule, microcapsule, or sustained-release capsule.

42A) A pharmaceutical composition for parenteral administrationcomprising the crystal according to any one of the above items 4A) to11A).

43A) A pharmaceutical composition for parenteral administrationcomprising the crystal according to any one of the above items 16A) to19A).

44A) The pharmaceutical composition according to the above item 42A),for dermal, subcutaneous, intravenous, intraarterial, intramuscular,intraperitoneal, transmucosal, inhalation, transnasal, ophthalmic, innerear, or vaginal administration.

45A) The pharmaceutical composition according to the above item 43A),for dermal, subcutaneous, intravenous, intraarterial, intramuscular,intraperitoneal, transmucosal, inhalation, transnasal, ophthalmic, innerear, or vaginal administration.

46A) The pharmaceutical composition according to the above item 42A) or44A), which is an injection, infusion, eye drop, nose drop, ear drop,aerosol, inhalation, lotion, impregnation, liniment, mouthwash, enema,ointment, plaster, jelly, cream, patch, cataplasm, external powder, orsuppository.

47A) The pharmaceutical composition according to the above item 43A) or45A), which is an injection, infusion, eye drop, nose drop, ear drop,aerosol, inhalation, lotion, impregnation, liniment, mouthwash, enema,ointment, plaster, jelly, cream, patch, cataplasm, external powder, orsuppository.

48A) A pharmaceutical composition for parenteral administrationcomprising the crystal according to any one of the above items 4A) to11A).

49A) A pharmaceutical composition for parenteral administrationcomprising the crystal according to any one of the above items 16A) to19A).

50A) A compound represented by Formula (II):

or a pharmaceutically acceptable salt, or solvate thereof.

51A) The salt or solvate according to the above item 50A), wherein thesalt is di-p-toluenesulfonate.

52A) A crystal of di-p-toluenesulfonate of a compound represented byFormula (II)

53A) The crystal according to the above item 52A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:6.4°±0.2°, 7.3°±0.2°, 21.1°±0.2°, 24.7°±0.2°, and 25.3°±0.2°.

54A) The crystal according to the above item 52A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:6.4°±0.2°, 7.3°±0.2°, 11.4°±0.2°, 15.2°±0.2°, 17.6°±0.2°, 20.1°±0.2°,21.1°±0.2°, 21.7°±0.2°, 24.7°±0.2°, and 25.3°±0.2°.

55A) A crystal of di-p-toluenesulfonate dihydrate of a compoundrepresented by Formula (II).

56A) The crystal according to the above item 55A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:7.3°±0.2°, 17.0°±0.2°, 18.5°±0.2°, 22.6°±0.2°, and 24.0°±0.2°.

57A) The crystal according to the above item 55A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:7.3°±0.2°, 17.0°±0.2°, 18.5°±0.2°, 19.7°±0.2°, 21.7°±0.2°, 22.60°±0.2°,22.8°±0.2°, 24.0°±0.2°, 24.8°±0.2°, and 29.7°±0.2°.

58A) The crystal according to the above item 5A), characterized by X-raypowder diffraction spectrum substantially in accordance with FIG. 1.

59A) The crystal according to the above item 5A), characterized by X-raypowder diffraction spectrum substantially in accordance with FIG. 2.

60A) The crystal according to the above item 5A), characterized by X-raypowder diffraction spectrum substantially in accordance with FIG. 3.

61A) The crystal according to the above item 5A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:11.3°±0.2°, 17.1°±0.2°, 25.5°±0.2°, 25.8°±0.2°, and 26.4°±0.2°.

62A) The crystal according to the above item 5A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:5.3°±0.2°, 11.3°±0.2°, 17.1°±0.2°, 18.8°±0.2°, 21.7°±0.2°, 23.2°±0.2°,25.5°±0.2°, 25.8°±0.2°, 26.4°±0.2°, and 29.4%° 0.2°.

63A) The crystal according to the above item 5A), characterized by X-raypowder diffraction spectrum substantially in accordance with FIG. 12.

64A) The crystal according to the above item 5A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:5.1°±0.2°, 9.9°±0.2°, 15.3°±0.2°, 21.4°±0.2°, and 23.3°±0.2°.

65A) The crystal according to the above item 5A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:5.1°±0.2°, 5.6°±0.2°, 9.2°±0.2°, 9.9°±0.2°, 14.4°±0.2°, 15.3°±0.2°,21.4°±0.2°, 22.6°±0.2°, and 23.3°±0.2°.

66A) The crystal according to the above item 5A), characterized by X-raypowder diffraction spectrum substantially in accordance with FIG. 13.

67A) The crystal according to the above item 5A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:7.0°±0.2°, 12.3°±0.2°, 16.0°±0.2°, 19.1°±0.2°, and 21.2°±0.2°.

68A) The crystal according to the above item 5A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:5.7°±0.2°, 7.0°±0.2°, 11.4°±0.2°, 12.3°±0.2°, 16.0°±0.2°, 17.3°±0.2°,19.1°±0.2°, 21.2°±0.2°, and 23.0°±0.2°.

69A) The crystal according to the above item 5A), characterized by X-raypowder diffraction spectrum substantially in accordance with FIG. 14.

70A) A crystal of monohydrochloride ethanolate of a compound representedby Formula (I).

71A) The crystal according to the above item 70A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:8.3°±0.2°, 8.9°±0.2°, 12.9°±0.2°, 13.7°±0.2°, and 14.7°±0.2°.

72A) The crystal according to the above item 70A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:7.6°±0.2°, 8.3°±0.2°, 8.9°±0.2°, 12.9°±0.2°, 13.7°±0.2°, 14.7°±0.2°,21.1°±0.2°, 21.5°±0.2°, 23.0°±0.2°, and 23.7°±0.2°.

73A) The crystal according to the above item 70A), characterized byX-ray powder diffraction spectrum substantially in accordance with FIG.15.

82A) The crystal according to the above item 17A), characterized byX-ray powder diffraction spectrum substantially in accordance with FIG.18.

83A) A crystal of monosulfate of a compound represented by Formula (I).

84A) The crystal according to the above item 83A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:6.2°±0.2°, 14.0°±0.2°, 14.5°±0.2°, 16.8°±0.2°, and 22.9°±0.2°.

85A) The crystal according to the above item 83A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:6.2°±0.2°, 12.1°±0.2°, 14.0°±0.2°, 14.5°±0.2°, 15.9°±0.2°, 16.2°±0.2°,16.8°±0.2°, 21.0°±0.2°, 22.9°±0.2°, and 26.9°±0.2°.

86A) The crystal according to the above item 83A), characterized byX-ray powder diffraction spectrum substantially in accordance with FIG.19.

87A) A crystal of monosulfate monohydrate of a compound represented byFormula (I).

88A) The crystal according to the above item 87A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:5.0°±0.2°, 9.9°±0.2°, 13.8%° 0.2°, 14.7°±0.2°, and 17.0°±0.2°.

89A) The crystal according to the above item 87A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:5.0°±0.2°, 7.4°±0.2°, 9.9°±0.2°, 10.1°±0.2°, 13.8°±0.2°, 14.7°±0.2°,17.0°±0.2°, and 21.4°±0.2°.

90A) The crystal according to the above item 87A), characterized byX-ray powder diffraction spectrum substantially in accordance with FIG.20.

91A) A crystal of monophosphate of a compound represented by Formula(I).

92A) The crystal according to the above item 91A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:5.1°±0.2°, 6.2°±0.2°, 6.7°±40.2°, 9.8°±0.2°, and 12.3°±0.2°.

93A) The crystal according to the above item 91A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:5.1°±0.2°, 6.2°±0.2°, 6.7°±0.2°, 9.8°±0.2°, 12.3°±0.2°, 13.3°±0.2°,16.6°±0.2°, and 21.1°±0.2°.

94A) The crystal according to the above item 91A), characterized byX-ray powder diffraction spectrum substantially in accordance with FIG.21.

95A) A crystal of monophosphate dihydrate of a compound represented byFormula (I).

96A) The crystal according to the above item 95A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:5.1°±0.2°, 6.5°±0.2°, 9.6°±0.2°, 12.9°±0.2°, and 18.6°±0.2°.

97A) The crystal according to the above item 95A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:5.1°±0.2°, 6.5°±0.2°, 9.6°±0.2°, 10.0°±0.2°, 11.9°±0.2°, 12.2°±0.2°,12.9°±0.2°, 16.9°±0.2°, and 18.6°±0.2°.

98A) The crystal according to the above item 95A), characterized byX-ray powder diffraction spectrum substantially in accordance with FIG.22.

99A) A crystal of monofumarate of a compound represented by Formula (I).

100A) The crystal according to the above item 99A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:8.0°±0.2°, 9.1°±0.2°, 16.1°±0.2°, 19.5°±0.2°, and 19.9°±0.2°.

101A) The crystal according to the above item 99A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:5.4°±0.2°, 6.0°±0.2°, 8.0°±0.2°, 9.1°±0.2°, 10.0°±0.2°, 12.3°±0.2°,14.8°±0.2°, 16.1%° 0.2°, 19.5°±0.2°, and 19.9°±0.2°.

102A) The crystal according to the above item 99A), characterized byX-ray powder diffraction spectrum substantially in accordance with FIG.23.

103A) The crystal according to the above item 99A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:5.4°±0.2°, 9.1°±0.2°, 13.3°±0.2°, 13.7°±0.2°, and 18.1°-0.2°.

104A) The crystal according to the above item 99A), which exhibits X-raypowder diffraction spectrum having peaks at diffraction angles 2θ:5.4°±0.2°, 8.0°±0.2°, 9.1°±0.2°, 13.3°±0.2°, 13.7°±0.2°, 16.4°±0.2°,17.1°±0.2°, 18.1°±0.2°, 19.9°±0.2°, and 21.8°±0.2°.

105A) The crystal according to the above item 99A), characterized byX-ray powder diffraction spectrum substantially in accordance with FIG.24.

Effect of the Invention

The present invention provides an acid addition salt of a compoundrepresented by Formula (I) and crystals thereof. The crystals have goodstability and solubility, and can be used as an active ingredient forproducing a pharmaceutical product. Also, a pharmaceutical compositioncontaining the crystals of an acid addition salt of a compoundrepresented by Formula (I) of the present invention can be used as ananticancer agent.

Moreover, the present invention provides a compound represented byFormula (II), a pharmaceutically acceptable salt thereof, theirsolvates, or their crystals. The compound and the like are useful whenproducing an acid addition salt of a compound represented by Formula (I)and crystals thereof.

A free base of an acid addition salt or a solvate thereof of thecompound represented by Formula (I) of the present invention is acompound having usefulness as a medicament. Here, usefulness as amedicament includes good solubility, good metabolical stability,unlikeliness to induce drug-metabolizing enzymes, unlikeliness toinhibit drug-metabolizing enzymes that metabolize other pharmaceuticalagents, being a highly orally absorbable compound, unlikeliness toinhibit hERG, low clearance, and/or a sufficiently long half-life toexert medicinal effects.

The acid addition salt or solvate thereof of the compound represented byFormula (I) of the present invention or crystals thereof have usefulnessas a medicament. Here, usefulness as a medicament include highsolubility in water, high heat stability, low hygroscopicity, highphotostability, high solution stability, high storage stability, highcoloration stability, high light exposure stability, high stability whenlight is blocked, a low specific volume, unlikeliness to beelectrostatically charged, high condensability, good flowability, highcrystallinity, high filtration/centrifugation applicability, highsolvent removability, compatibility with industrially advantageoussolvents, and high compression-formability into tablets.

Also, the compound in solid form can substantially influence physicalproperties of the compound, including (1) packaging properties such asmolar volume, density, and hygroscopicity, (2) thermodynamic propertiessuch as melting temperature, vapor pressure, and solubility, (3) kineticproperties such as dissolution rate and stability (such as stabilityagainst humidity and stability in surroundings under storageconditions), (4) surface properties such as surface area, wettability,interfacial tension, and shape, (5) mechanical properties such ashardness, tensile strength, moldability, handleability, flowability(flow), and blendability (blend), or (6) filterability. Selection andcontrol of a solid form are important particularly for compounds thatserve as drugs. Careful selection and control of a solid form can reduceproblems involved in production, formulation, or administration of thecompound.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows X-ray powder diffraction pattern of monohydrochloridecrystal form I (Form I) of the compound represented by Formula (I). Thehorizontal axis represents 2θ(°), and the vertical axis representsintensity (Count).

FIG. 2 shows X-ray powder diffraction pattern of monohydrochloridecrystal form V (Form V) of the compound represented by Formula (I). Thehorizontal axis represents 2θ(°), and the vertical axis representsintensity (Count).

FIG. 3 shows X-ray powder diffraction pattern of monohydrochloridecrystal form VI (Form VI) of the compound represented by Formula (I).The horizontal axis represents 2θ(°), and the vertical axis representsintensity (Count).

FIG. 4 shows TG/DTA analysis result of monohydrochloride crystal form I(Form I) of the compound represented by Formula (I).

FIG. 5 shows TG/DTA analysis result of monohydrochloride crystal form V(Form V) of the compound represented by Formula (I).

FIG. 6 shows TG/DTA analysis result of monohydrochloride crystal form VI(Form VI) of the compound represented by Formula (I).

FIG. 7 shows DSC analysis result of monohydrochloride crystal form I(Form I) of the compound represented by Formula (I).

FIG. 8 shows DSC analysis result of monohydrochloride crystal form V(Form V) of the compound represented by Formula (I).

FIG. 9 shows DSC analysis result of monohydrochloride crystal form VI(Form VI) of the compound represented by Formula (I).

FIG. 10 shows X-ray powder diffraction pattern of di-p-toluenesulfonatecrystal of the compound represented by Formula (II). The horizontal axisrepresents 2θ(°), and the vertical axis represents intensity (Count).

FIG. 11 shows X-ray powder diffraction pattern of di-p-toluenesulfonatedihydrate crystal of the compound represented by Formula (II). Thehorizontal axis represents 2θ(°), and the vertical axis representsintensity (Count).

FIG. 12 shows X-ray powder diffraction pattern of monohydrochloridecrystal form II (Form II) of the compound represented by Formula (I).The horizontal axis represents 2θ(°), and the vertical axis representsintensity (Count).

FIG. 13 shows X-ray powder diffraction pattern of monohydrochloridecrystal form III (Form III) of the compound represented by Formula (I).The horizontal axis represents 2θ(°), and the vertical axis representsintensity (Count).

FIG. 14 shows X-ray powder diffraction pattern of monohydrochloridecrystal form VII (Form VII) of the compound represented by Formula (I).The horizontal axis represents 2θ(°), and the vertical axis representsintensity (Count).

FIG. 15 shows X-ray powder diffraction pattern of monohydrochlorideethanolate crystal of the compound represented by Formula (I). Thehorizontal axis represents 2θ(°), and the vertical axis representsintensity (Count).

FIG. 16 shows X-ray powder diffraction pattern of free base monohydratecrystal of the compound represented by Formula (I). The horizontal axisrepresents 2θ(°), and the vertical axis represents intensity (Count).

FIG. 17 shows X-ray powder diffraction pattern of free base trihydratecrystal of the compound represented by Formula (I). The horizontal axisrepresents 2θ(°), and the vertical axis represents intensity (Count).

FIG. 18 shows X-ray powder diffraction pattern ofmono-p-toluenesulfonate crystal form I (Form I) of the compoundrepresented by Formula (I). The horizontal axis represents 2θ(°), andthe vertical axis represents intensity (Count).

FIG. 19 shows X-ray powder diffraction pattern of monosulfate crystal ofthe compound represented by Formula (I). The horizontal axis represents2θ(°), and the vertical axis represents intensity (Count).

FIG. 20 shows X-ray powder diffraction pattern of monosulfatemonohydrate crystal of the compound represented by Formula (I). Thehorizontal axis represents 2θ(°), and the vertical axis representsintensity (Count).

FIG. 21 shows X-ray powder diffraction pattern of monophosphate crystalof the compound represented by Formula (I). The horizontal axisrepresents 2θ(°), and the vertical axis represents intensity (Count).

FIG. 22 shows X-ray powder diffraction pattern of monophosphatedihydrate crystal form I (Form 1) of the compound represented by Formula(I). The horizontal axis represents 2θ(°), and the vertical axisrepresents intensity (Count).

FIG. 23 shows X-ray powder diffraction pattern of monofumarate crystalform I (Form I) of the compound represented by Formula (I). Thehorizontal axis represents 2θ(°), and the vertical axis representsintensity (Count).

FIG. 24 shows X-ray powder diffraction pattern of monofumarate crystalform II (Form II) of the compound represented by Formula (I). Thehorizontal axis represents 2θ(°), and the vertical axis representsintensity (Count).

FIG. 25 shows TG/DTA analysis result of monohydrochloride crystal formII (Form II) of the compound represented by Formula (I).

FIG. 26 shows TG/DTA analysis result of monohydrochloride crystal formIII (Form III) of the compound represented by Formula (I).

FIG. 27 shows TG/DTA analysis result of monohydrochloride crystal formVII (Form VII) of the compound represented by Formula (I).

FIG. 28 shows TG/DTA analysis result of monohydrochloride ethanolatecrystal of the compound represented by Formula (I).

FIG. 29 shows TG/DTA analysis result of free base monohydrate crystal ofthe compound represented by Formula (I).

FIG. 30 shows TG/DTA analysis result of free base trihydrate crystal ofthe compound represented by Formula (I).

FIG. 31 shows TG/DTA analysis result of mono-p-toluenesulfonate crystalform I (Form I) of the compound represented by Formula (I).

FIG. 32 shows TG/DTA analysis result of monosulfate crystal of thecompound represented by Formula (I).

FIG. 33 shows TG/DTA analysis result of monosulfate monohydrate crystalof the compound represented by Formula (I).

FIG. 34 shows TG/DTA analysis result of monophosphate crystal of thecompound represented by Formula (I).

FIG. 35 shows TG/DTA analysis result of monophosphate dihydrate crystalform I (Form I) of the compound represented by Formula (I).

FIG. 36 shows TG/DTA analysis result of monofumarate crystal form I(Form I) of the compound represented by Formula (I).

FIG. 37 shows TG/DTA analysis result of monofumarate crystal form II(Form II) of the compound represented by Formula (I).

FIG. 38 shows X-ray powder diffraction pattern of dihydrochloridecrystal of the compound represented by Formula (I). The horizontal axisrepresents 2θ(°), and the vertical axis represents intensity (Count).

FIG. 39 shows X-ray powder diffraction pattern ofmono-p-toluenesulfonate crystal form II (Form II) of the compoundrepresented by Formula (I). The horizontal axis represents 2θ(°), andthe vertical axis represents intensity (Count).

FIG. 40 shows X-ray powder diffraction pattern of monobenzenesulfonatecrystal of the compound represented by Formula (I). The horizontal axisrepresents 2θ(°), and the vertical axis represents intensity (Count).

FIG. 41 shows X-ray powder diffraction pattern of monophosphatedihydrate crystal form II (Form II) of the compound represented byFormula (I). The horizontal axis represents 2θ(°), and the vertical axisrepresents intensity (Count).

FIG. 42 shows X-ray powder diffraction pattern of monocitrate crystal ofthe compound represented by Formula (I). The horizontal axis represents2θ(°), and the vertical axis represents intensity (Count).

FIG. 43 shows X-ray powder diffraction pattern of monotartrate crystalof the compound represented by Formula (I). The horizontal axisrepresents 2θ(°), and the vertical axis represents intensity (Count).

FIG. 44 shows X-ray powder diffraction pattern of free base crystal ofthe compound represented by Formula (I). The horizontal axis represents2θ(°), and the vertical axis represents intensity (Count).

FIG. 45 shows moisture sorption and desorption isotherms ofmonohydrochloride crystal form I (Form I) of the compound represented byFormula (I). The vertical axis represents the ratio of increased mass tomass at 0% Target % P/P₀ [Change In Mass, Unit: %], and the horizontalaxis represents relative humidity [Target % P/P₀, Unit: %]. The curveplotted with ♦ is a moisture sorption isotherm, and the curve plottedwith ▪ is a moisture desorption isotherm.

FIG. 46 shows moisture sorption and desorption isotherms ofmonohydrochloride crystal form V (Form V) of the compound represented byFormula (I). The vertical axis represents the ratio of increased mass tomass at 0% Target % P/P₀ [Change In Mass, Unit: %], and the horizontalaxis represents relative humidity [Target % P/P₀, Unit: %]. The curveplotted with ♦ is a moisture sorption isotherm, and the curve plottedwith ▪ is a moisture desorption isotherm.

FIG. 47 shows moisture sorption and desorption isotherms ofmonohydrochloride crystal form VI (Form VI) of the compound representedby Formula (I). The vertical axis represents the ratio of increased massto mass at 0% Target % P/P₀ [Change In Mass, Unit: %], and thehorizontal axis represents relative humidity [Target % P/P₀, Unit: %].The curve plotted with ♦ is a moisture sorption isotherm, and the curveplotted with ▪ is a moisture desorption isotherm.

FIG. 48 shows moisture sorption and desorption isotherms ofmonohydrochloride crystal form II (Form II) of the compound representedby Formula (I). The vertical axis represents the ratio of increased massto mass at 0% Target % P/P₀ [Change In Mass, Unit: %], and thehorizontal axis represents relative humidity [Target % P/P₀, Unit: %].The curve plotted with ♦ is a moisture sorption isotherm, and the curveplotted with ▪ is a moisture desorption isotherm.

FIG. 49 shows moisture sorption and desorption isotherms ofmono-p-toluenesulfonate crystal form I (Form I) of the compoundrepresented by Formula (I). The vertical axis represents the ratio ofincreased mass to mass at 0% Target % P/P₀ [Change In Mass, Unit: %],and the horizontal axis represents relative humidity [Target % P/P₀,Unit: %]. The curve plotted with ♦ is a moisture sorption isotherm, andthe curve plotted with ▪ is a moisture desorption isotherm.

FIG. 50 shows moisture sorption and desorption isotherms of monosulfatecrystal of the compound represented by Formula (I). The vertical axisrepresents the ratio of increased mass to mass at 0% Target % P/P₀[Change In Mass, Unit: %], and the horizontal axis represents relativehumidity [Target % P/P₀, Unit: %]. The curve plotted with ♦ is amoisture sorption isotherm, and the curve plotted with ▪ is a moisturedesorption isotherm.

FIG. 51 shows TG/DTA analysis result of free base crystal of thecompound represented by Formula (I).

FIG. 52 shows moisture sorption and desorption isotherms of free basecrystal of the compound represented by Formula (I). The vertical axisrepresents the ratio of increased mass to mass at 0% Target % P/P₀[Change In Mass, Unit: %], and the horizontal axis represents relativehumidity [Target % P/P₀, Unit: %]. The curve plotted with ♦ is amoisture sorption isotherm, and the curve plotted with ▪ is a moisturedesorption isotherm.

FIG. 53 shows X-ray powder diffraction pattern of dibenzenesulfonate ofthe compound represented by Formula (II). The horizontal axis represents2θ(°), and the vertical axis represents intensity (Count).

MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention is described by providingembodiments. Throughout the specification, singular forms should beunderstood as including their plural forms unless indicated otherwise.Accordingly, singular articles (such as “a”, “an”, and “the” in the caseof English) should be understood as including plural concepts unlessindicated otherwise. Also, the terms used herein should be understood asbeing used in their meanings commonly used in the art unless indicatedotherwise. Accordingly, unless defined otherwise, all technical termsand scientific terms as used herein have the same meanings as thosecommonly understood by people having ordinary skill in the art to whichthe present invention pertains. In the case of contradiction, thepresent specification (including definitions) controls.

The meanings of the terms used herein are explained below. A term isused to provide the same meaning no matter when it is used alone or usedin combination with other terms.

The term of “consisting of” means having only components.

The term of “comprising” means not restricting with components and notexcluding undescribed factors.

The “anticancer agent” and “therapeutic agent for cancer” as used hereinencompass therapeutic agents for brain tumor (such as glioblastoma),urological cancer (such as bladder cancer and renal cancer), genitalcancer (such as prostate cancer, ovarian cancer, and uterine cancer),lymphatic tumor, gastrointestinal cancer (such as stomach cancer,esophageal cancer, large intestine cancer, and colon cancer), throatcancer, lung cancer (such as lung adenocarcinoma, small cell lungcancer, non-small cell lung cancer), pancreatic cancer, breast cancer,head and neck cancer, and thyroid cancer. In particular, the anticanceragent and the therapeutic agent for cancer are preferably used astherapeutic agents for breast cancer, brain tumor, bladder cancer,kidney cancer, prostate cancer, ovarian cancer, uterine cancer, lungcancer, pancreatic cancer, and head and neck cancer.

The present invention encompasses a method for treating or preventingcancer in a mammal in need of treating or preventing cancer, and themethod comprising of administering to the mammal a therapeuticallyeffective amount of crystals of an acid addition salt of the compoundrepresented by Formula (I) or a pharmaceutical composition containingthe crystals. Cancer to be preferably treated is selected from braintumor (such as glioblastoma), urological cancer (such as bladder cancerand renal cancer), genital cancer (such as prostate cancer, ovariancancer, and uterine cancer), lymphatic tumor, gastrointestinal cancer(such as stomach cancer, esophageal cancer, large intestine cancer, andcolon cancer), throat cancer, lung cancer (such as lung adenocarcinoma,small cell lung cancer, non-small cell lung cancer), pancreatic cancer,breast cancer, head and neck cancer, and thyroid cancer. More preferableare breast cancer, brain tumor, bladder cancer, kidney cancer, prostatecancer, ovarian cancer, uterine cancer, lung cancer, pancreatic cancer,and head and neck cancer. Even more preferable is breast cancer.

One or more hydrogen, carbon, and/or other atoms of the compoundrepresented by Formula (I) or Formula (II) may be substituted withisotopes of hydrogen, carbon, and/or other atoms, respectively. Examplesof such isotopes encompass hydrogen, carbon, nitrogen, oxygen,phosphorus, sulfur, fluorine, iodine, and chlorine, such as ²H, ³H, ¹¹C,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ¹²³I, and ³⁶Cl,respectively. The compounds represented by Formula (I) or Formula (II)encompass compounds substituted with such isotopes. Isotope-substitutedcompounds are also useful as pharmaceutical products, and allradiolabeled forms of the compounds represented by Formula (I) orFormula (II) are encompassed. Also, a “radiolabeling method” forproducing the “radiolabeled form” is encompassed within the presentinvention, and the “radiolabeled form” is useful as a research and/ordiagnostic tool in metabolic pharmacokinetic studies and binding assays.

The radiolabeled form of the compound represented by Formula (I) orFormula (II) can be prepared by methods well known in the art. Forexample, a tritium-labeled compound represented by Formula (I) orFormula (II) can be prepared by introducing tritium into a specificcompound represented by Formula (I) or Formula (II) by a catalyticdehalogenation reaction using tritium. This method encompasses reactingtritium gas and a precursor, which is obtained by substituting acompound represented by Formula (I) or Formula (II) with a halogensuitably, in the presence of a suitable catalyst such as Pd/C in thepresence or absence of a base. For another suitable method for preparinga tritium-labeled compound, “Isotopes in the Physical and BiomedicalSciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)” can bereferred to. A ¹⁴C-labeled compound can be prepared by using a rawmaterial having ¹⁴C carbon.

Examples of pharmaceutically acceptable salts of the compoundrepresented by Formula (I) or Formula (II) include salts of the compoundrepresented by Formula (I) or Formula (II) and inorganic acids (such ashydrochloric acid, sulfuric acid, nitric acid, carbonic acid,hydrobromic acid, phosphoric acid, and hydroiodic acid) and organicacids (such as formic acid, acetic acid, propionic acid, trifluoroaceticacid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid,fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid,phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonicacid, methanesulfonic acid, and ethanesulfonic acid). In particular,examples include salts of hydrochloric acid, p-toluenesulfonic acid,sulfuric acid, phosphoric acid, fumaric acid, tartaric acid, andmethanesulfonic acid. These salts can be formed by commonly performedmethods.

Hydrochloride, p-toluenesulfonate, or other pharmaceutically acceptablesalts of the compound represented by Formula (I) or pharmaceuticallyacceptable salts of the compound represented by Formula (II) of thepresent invention may form solvates (such as hydrates and ethanolates),co-crystals, and/or crystal polymorphs, and the present inventionencompasses such various solvates, co-crystals, and crystal polymorphsas well. In the “solvate”, any number of solvent molecules (such aswater molecules) may be coordinated with hydrochloride,p-toluenesulfonate, or other pharmaceutically acceptable salts of thecompound represented by Formula (I) or pharmaceutically acceptable saltsof the compound represented by Formula (II). By being left to stand inthe atmosphere, hydrochloride, p-toluenesulfonate, or otherpharmaceutically acceptable salts of the compound represented by Formula(I) or pharmaceutically acceptable salts of the compound represented byFormula (II) may absorb water, resulting in attachment of adsorbed wateror formation of hydrates. Also, recrystallization of hydrochloride,p-toluenesulfonate, or other pharmaceutically acceptable salts of thecompound represented by Formula (I) or pharmaceutically acceptable saltsof the compound represented by Formula (II) may form crystal polymorphs.The “co-crystal” means that hydrochloride, p-toluenesulfonate, or otherpharmaceutically acceptable salts of the compound represented by Formula(I) or pharmaceutically acceptable salts of the compound represented byFormula (II) and counter molecules are present within the same crystallattice, and may be formed with any number of counter molecules.

Hydrochloride, p-toluenesulfonate, or other pharmaceutically acceptablesalts of the compound represented by Formula (I) or solvates thereof ofthe present invention may form prodrugs, and the present inventionencompasses such various prodrugs as well. The prodrug is a derivativeof the compound of the present invention having a chemically ormetabolically decomposable group, and is a compound that becomes apharmacologically active compound of the present invention by solvolysisor in vivo under physiological conditions. The prodrug encompasses acompound that is converted into the compound represented by Formula (I)by enzymatic oxidation, reduction, hydrolysis, or the like underphysiological conditions in a living body, and a compound that isconverted into the compound represented by Formula (I) by hydrolysis dueto gastric acid or the like. A method for selecting and a method forproducing an appropriate prodrug derivative are described in, forexample, “Design of Prodrugs, Elsevier, Amsterdam, 1985”. The prodrugmay itself have activity.

The compound represented by Formula (I):

is an EGF receptor/HER2 dual inhibitor described in Patent Document 1,and a pharmaceutical composition containing the compound is useful forpreventing or treating cancer. The compound represented by Formula (I)can be prepared according to the method described in Patent Document 1or 2.

Specifically, the compound represented by Formula (I) can be produced byreacting the compound represented by the following formula:

with the compound represented by the following formula:

under acidic conditions, and neutralizing the resulting crude product.

Alternatively, the compound represented by Formula (I) can be producedby reacting the compound represented by the following formula:

with the compound represented by the following formula:

or salt thereof or their solvates under acidic conditions, andneutralizing the resulting crude product.

For example, free base A of compound (I) and free base B of compound (I)can be produced as the compound represented by Formula (I) by the methoddescribed in the Examples herein.

Then, the obtained compound represented by Formula (I):

is dissolved in various organic solvents and crystallized under acidicconditions, and thereby an acid addition salt of the compoundrepresented by Formula (I) or crystals thereof can be produced.

Examples of acids include inorganic acids (such as hydrochloric acid,sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoricacid, and hydroiodic acid) and organic acids (such as formic acid,acetic acid, propionic acid, trifluoroacetic acid, citric acid, lacticacid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelicacid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbicacid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonicacid, and ethanesulfonic acid). In particular, examples includehydrochloric acid and p-toluenesulfonic acid.

In monohydrochloride of the compound represented by Formula (I), thereare Form I, Form II, Form III, Form V, Form VI and Form VII, andethanolate crystal forms. Also, there are crystal forms ofmono-p-toluenesulfonate; monosulfate and monosulfate hydrate;monophosphate and monophosphate hydrate; and monofumarate of thecompound represented by Formula (I). These crystal polymorphs can beproduced in a differentiated manner according to the type of organicsolvent used for crystallization and which of free base A of thecompound represented by Formula (I) or free base B of the compoundrepresented by Formula (I) is used as the compound represented byFormula (I).

Monohydrochloride crystals Form I of the compound represented by Formula(I) can be produced by dissolving free base A of the compoundrepresented by Formula (I) in methanol and causing crystallization inthe presence of hydrochloric acid.

Monohydrochloride crystals Form II of the compound represented byFormula (I) can be produced by dissolving free base A of the compoundrepresented by Formula (I) in a mixed solvent of methanol and ethylacetate (methanol:ethyl acetate=1:1) and causing crystallization in thepresence of hydrochloric acid.

Monohydrochloride crystals Form III of the compound represented byFormula (I) can be produced by dissolving free base A of the compoundrepresented by Formula (I) in a mixed solvent of methanol and ethylacetate (methanol:ethyl acetate=1:4) and causing crystallization in thepresence of hydrochloric acid.

Monohydrochloride crystals Form V of the compound represented by Formula(I) can be produced by dissolving free base B of the compoundrepresented by Formula (I) in 2-propanol and causing crystallization inthe presence of acid.

Monohydrochloride crystals Form VI of the compound represented byFormula (I) can be produced by dissolving free base A of the compoundrepresented by Formula (I) in 2-propanol and causing crystallization inthe presence of hydrochloric acid.

Monohydrochloride crystals Form VII of the compound represented byFormula (I) can be produced by dissolving crystal form VI ofmonohydrochloride of the compound represented by Formula (I) in1,2-dimethoxyethane and causing crystallization.

Monohydrochloride ethanolate crystals of the compound represented byFormula (I) can be produced by adding monohydrochloride crystal Form Ias seed crystals to a mixed solution of ethyl acetate and ethanol.

Free base crystals of the compound represented by Formula (I) can beproduced by dissolving free base B of the compound represented byFormula (I) in a mixed solution of hexane and ethyl acetate and causingcrystallization.

Mono-p-toluenesulfonate crystal Form I of the compound represented byFormula (I) can be produced by purifying free base A of the compoundrepresented by Formula (I) by an ordinary method, dissolving the freebase in ethyl acetate, adding 1 mol/L of a solution of p-toluenesulfonicacid in methanol, and causing crystallization.

Monosulfate crystals of the compound represented by Formula (I) can beproduced by dissolving free base A of the compound represented byFormula (I) in acetonitrile, adding 1 mol/L of sulfuric acid inmethanol, and causing crystallization.

Monosulfate monohydrate crystals of the compound represented by Formula(I) can be produced by dissolving trihydrate crystals of the compoundrepresented by Formula (I) in a mixed solution of acetonitrile and2-propanol, adding 0.1 mol/L of sulfuric acid, then concentrating themixture, further, adding a mixed solution of methanol and water, andshaking and then concentrating the mixture.

Monophosphate crystals of the compound represented by Formula (I) can beproduced by dissolving trihydrate crystals of the compound representedby Formula (I) in a mixed solution of acetonitrile and 2-propanol,adding 0.1 mol/L of phosphoric acid, then concentrating the mixture,further, adding a mixed solution of ethanol and water, and shaking andthen concentrating the mixture.

Monophosphate dihydrate crystal Form I of the compound represented byFormula (I) can be produced by dissolving trihydrate crystals of thecompound represented by Formula (I) in a mixed solution of acetonitrileand 2-propanol, adding 0.1 mol/L of phosphoric acid, then concentratingthe mixture, further, adding a mixed solution of methanol and water, andshaking and then concentrating the mixture.

Monofumarate crystal Form I of the compound represented by Formula (I)can be produced by dissolving trihydrate crystals of the compoundrepresented by Formula (I) in a mixed solution of acetonitrile and2-propanol, adding 0.1 mol/L of a mixed solution of fumaric acid inmethanol and water, then concentrating the mixture, further, addingmethanol and water, and shaking and then concentrating the mixture.

Monofumarate crystal Form II of the compound represented by Formula (I)can be produced by dissolving trihydrate crystals of the compoundrepresented by Formula (I) in a mixed solution of acetonitrile and2-propanol, adding 0.1 mol/L of a mixed solution of fumaric acid inmethanol and water, then concentrating the mixture, further, addingacetonitrile and water, and shaking and then concentrating the mixture.

Hereinafter, methods for identifying the crystals of the presentinvention are described.

Unless otherwise noted, the numerical values provided in the descriptionand the claims are approximate values. Numerical values vary due to theequipment calibration, equipment errors, purity of materials, crystalsize, and sample size, among other factors.

As used herein, the “crystal” means a substance having an orderedarrangement of atoms, ions, molecules and the like that constitute asolid, and accordingly the substance has periodism and anisotropism. Thedegree of crystallinity of a crystal form can be determined by varioustechniques including, for example, X-ray powder diffractometry, moisturesorption desorption, differential scanning calorimetry,thermogravimetry/differential thermal analysis, solution colorimetry,and dissolution properties.

X-Ray Powder Diffraction (XRPD)

In general, crystalline organic compounds consist of a large number ofatoms that are arranged in a periodic array in three-dimensional space.The structural periodicity normally manifests physical properties, whichcan be explicitly distinguished by most spectroscopic probes (e.g.,X-ray diffraction, an infrared spectrum, a Raman spectrum and solidstate NMR). The X-ray powder diffraction (XRPD) is acknowledged to beone of the most sensitive analytical methods for measuring solidcrystallinity. X-rays which are irradiated to crystals are reflected bythe crystal lattice planes and mutually interfere. Then, only thediffraction lines in the direction which fulfill the conditionspredicted by Bragg's law are intensified and the ordered diffractionlines corresponding to the periodicity of the structure are observed. Onthe other hand, in the case of amorphous solids, the well-ordereddiffraction lines over a long-range are not observed. Amorphous solidsusually show non-characteristic broad XRPD patterns, because they do nothave the ordered iteration periodicity in the structure, so that thediffraction phenomenon does not occur.

The crystal forms of acid addition salts of the compound represented byFormula (I) disclosed herein preferably have distinguishable X-raypowder diffraction profiles. For example, crystals containingmonohydrochloride or mono-p-toluenesulfonate of the compound representedby Formula (I) preferably are distinguishable from other crystal formsaccording to the presence of characteristic diffraction peaks. Thecharacteristic diffraction peaks as used herein are peaks selected fromthe observed diffraction patterns. The characteristic diffraction peaksare selected from preferably about 20, more preferably about 10, andmost preferably about 5 peaks in a diffraction pattern.

In general, diffraction angles (2θ) in X-ray powder diffraction may havea margin of error within a range of ±0.2°, the value of a diffractionangle in X-ray powder diffraction should be understood as includingvalues within a range of around ±0.2°. Therefore, the present inventionincludes not only crystals whose diffraction angles of the peaks inX-ray powder diffraction perfectly match, but also crystals whosediffraction angles of the peaks match within an error of around ±0.2°.

In general, it is known that the absolute intensities and the relativeintensities of the peaks shown in the Tables and Figures below may varydue to many factors such as selected orientation effects of crystals inthe X-ray beam, effect of coarse particle, purity of the material beinganalyzed or degree of crystallinity of the sample, for example. The peakpositions may also shift for variations in sample height. Furthermore,measurements using a different wavelength will result in differentshifts according to the Bragg equation (nλ=2d sin θ). Different XRPDpatterns obtained by using such different wavelengths are also withinthe scope of the present invention.

TG/DTA (Thermogravimetry/Differential Thermal Analysis)

TG/DTA is one of the main measuring methods for thermal analysis, and isa method for measuring the weight and the thermal properties of thesubstance as an aggregate of an atom(s) and a molecule(s).

TG/DTA is the method for measuring a temperatures or changes in weightand heat capacity over time of a pharmaceutical active ingredient. TG(thermo gravity) and DTA (differential thermal analysis) curve areobtained by plotting the obtained data against temperature or time.TG/DTA curve provides the information about the changes in weight andheat capacity related to decomposition, dehydration, oxidation,reduction, sublimation and evaporation of an active pharmaceuticalingredient.

It is known that the temperature and the weight changes observed inTG/DTA may depend on the heating rate, sample preparation technique andspecific device. Therefore, in TG/DTA, a “melting point” means onsettemperature which is unaffected by technique for preparing the sample.In identifying a crystal, the melting point as well as the overallpattern is important and may change somewhat depending on a measurementcondition and apparatus.

DSC (Differential Scanning Calorimetry)

DSC is one of the main measuring methods for thermal analysis, and is amethod for measuring the thermal properties of the substance as anaggregate of an atom(s) and a molecule(s). A differential scanningcalorimetry curve can be obtained by measuring temperatures or change ofheat capacity over time of an active pharmaceutical ingredient by DSC,and plotting the obtained data to temperatures or times. From adifferential scanning calorimetry curve, the information about the onsettemperature, melting endothermic maximum and enthalpy of an activepharmaceutical ingredient can be obtained.

As to DSC, it is known that the observed temperature can depend on therate of temperature change, the sample preparations techniques or thespecific devices. Therefore, in DSC, “the melting point” means the onsettemperature which is unaffected by technique for preparing the sample.The error span in the onset temperature obtained from a differentialscanning calorimetry curve is approximately ±2° C. In identifying acrystal, the melting point as well as the overall pattern is importantand may change somewhat depending on a measurement condition andapparatus.

(Moisture Sorption-Desorption Isothermal Measurement)

Moisture sorption-desorption isothermal measurement is measuring theweight changes of a subject solid under various relative humidityconditions, and is a method for determining moisture sorption-desorptionbehaviors.

As a basic measurement method, the relative humidity is increased inincrements of 5% or 10% based on the dry weight at 0% Target % P/P₀(relative humidity 0%), and after the weights at respective relativehumidities are stabilized, the amount of adsorbed water can be obtainedfrom the weight increased from a reference value. Similarly, it ispossible to measure the amount of desorbed water by reducing therelative humidity in increments of 5% or 10% from 100% Target % P/P₀.

Sorption and desorption isotherms can be obtained by plotting the weightchange values at respective relative humidities. From the results, it ispossible to investigate the sorption and desorption phenomena ofattached moisture at respective humidities. Also, when anhydridecrystals and hydrate crystals undergo mutual crystal transition due tohumidity, it is possible to calculate the humidity, at which crystaltransition occurs, and the amount of water of crystallization.

Since the sorption and desorption of attached water and water ofcrystallization are affected by the particle size, degree ofcrystallinity, crystal habit, and the like, the measurement results mayslightly vary.

(Photostability Test)

The photostability test is one of the methods for measuring chemical orphysicochemical changes of an active pharmaceutical ingredient or apharmaceutical preparation caused by light exposure to evaluateproperties of a sample with respect to light. In the photostabilitytest, a sample such as an active pharmaceutical ingredient or apharmaceutical preparation is irradiated with light at a specifiedoutput for a certain period of time. Properties of the sample withrespect to light can be evaluated by analyzing the impurities andanalogous substances, crystal form, color difference, and the like ofthe sample by scientific techniques (such as high performance liquidchromatography, X-ray crystal diffraction, and colorimetry) when aspecified total illuminance is reached. In order to verify that aspecified amount of light exposure is attained, the amount of lightexposure is managed using a radiometer or a luminometer, and a test iscarried out using an actinometric system.

The pharmaceutical composition containing an acid addition salt orcrystals of the acid addition salt of the compound represented byFormula (I) of the present invention is highly useful as a therapeuticagent or a prophylactic agent for cancer.

The acid addition salt or crystals of the acid addition salt of thecompound represented by Formula (I) of the present invention can beadministered to a human patient as-is, or can be administered as apharmaceutical composition obtained by mixing the crystals with asuitable carrier or excipient. Drug formulation and administrationtechniques are suitably selected and used by combining pharmaceuticalformulations and techniques known to those skilled in the art.

Routes of administration of the acid addition salt or crystals of theacid addition salt of the compound represented by Formula (I) or thepharmaceutical composition containing them of the present invention caninclude, but are not limited to, oral, rectal, transmucosal or enteraladministrations, or intramuscular, subcutaneous, intraspinal,intrathecal, direct intraventricular, intravenous, intravitreal,intraperitoneal, intranasal, intraocular injections. Preferable routesof administration are oral or injection (intramuscular, subcutaneous,intraspinal, intrathecal, intravenous). A particularly preferable routeof administration is oral.

The pharmaceutical composition of the present invention can be producedby a production method well known in the art, such as commonly usedmixing, dissolution, granulation, sugar coat formation, powderization,emulsification, encapsulation, entrapment, and lyophilization processes.

The acid addition salt or crystals of the acid addition salt of thecompound represented by Formula (I) or the pharmaceutical compositioncontaining them of the present invention can be administered byinjection using an aqueous solution, preferably a physiologicallycompatible buffer such as Ringer's solution or physiological saline.

The acid addition salt or crystals of the acid addition salt of thecompound represented by Formula (I) or the pharmaceutical compositioncontaining them of the present invention can be transmucosallyadministered using a penetrant suitable for a barrier to be penetrated.A penetrant that is generally known in the art can be used.

The acid addition salt or crystals of the acid addition salt of thecompound represented by Formula (I) or the pharmaceutical composition,in which they are combined with a pharmaceutically acceptable carrierwell known in the art, of the present invention can be orallyadministered. By being combined with such a carrier, the acid additionsalt or crystals of the acid addition salt of the compound representedby Formula (I) of the present invention can be administered as a tablet,pill, lozenge, sugar-coated tablet, capsule, solution, gel, syrup, orsuspension. A pharmaceutical composition for oral administration can beformed by using a solid excipient, adding another suitable adjuvant ifdesired, then pulverizing the obtained mixture, and processing thegranular mixture to obtain a tablet or a core of a sugar-coated tablet.

Useful excipients are, in particular, fillers such as sugars includinglactose, sucrose, mannitol, or sorbitol, cellulose preparations of, forexample, corn starch, wheat starch, rice starch, and potato starch,gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose,and/or sodium carboxymethyl cellulose. If necessary, disintegrators suchas agar and alginic acid can be added. A salt such as sodium alginatecan be used as well.

Pharmaceutical compositions usable for oral administration includepush-fit capsules formed of gelatin, hermetically sealed capsules formedof gelatin and a plasticizer such as glycerol or sorbitol, and the like.Push-fit capsules can contain an active component mixed with a fillersuch as lactose, a binder such as starch, and/or a lubricant such astalc or magnesium stearate and, if desired, a stabilizer. In softcapsules, crystals of the acid addition salt of the compound representedby Formula (I) of the present invention can be dissolved or suspended ina suitable liquid such as fatty oil, liquid paraffin, or liquidpolyethylene glycol. A stabilizer can be added to these formulations aswell.

The pharmaceutical composition can also contain a suitable carrier orexcipient having a solid or gel phase. Examples of such carriers orexcipients include calcium carbonate, calcium phosphate, various sugars,starch, cellulose derivatives, gelatin, polymers such as polyethyleneglycol, and the like.

A therapeutically effective amount of the acid addition salt or crystalsof the acid addition salt of the compound represented by Formula (I) ofthe present invention can be initially estimated from a cell cultureassay. Then, a large dosage can be formulated for use in animal modelssuch that a circulating level range including IC50 (i.e., a level of theacid addition salt or crystals of the acid addition salt of the compoundrepresented by Formula (I) or the pharmaceutical composition containingthem of the present invention, which achieves inhibition of half of themaximal PK activity) determined in a cell culture is achieved. Then, anamount useful in humans can be more precisely determined using suchinformation.

The therapeutic effect of the acid addition salt or crystals of the acidaddition salt of the compound represented by Formula (I) or thepharmaceutical composition containing them of the present invention canbe measured by a standard pharmaceutical procedure in a cell culture oran experimental animal. For example, the therapeutic effect may beevaluated according to the biological test method described inInternational Publication No. WO2006/090717. Data obtained from such acell culture assay and an animal experiment can be used for formulatinga dosage range for use in humans. The dosage can be altered according tothe form of administration used and the route of administrationutilized. A precise route of administering a formulation and dosage canbe selected by individual physicians in consideration of patientconditions.

It is also an embodiment of the present invention that the acid additionsalt or crystals of the acid addition salt of the compound representedby Formula (I) or the pharmaceutical composition containing them of thepresent invention can be combined with another pharmaceutical agent fortreating a disease and a disorder. For example, the acid addition saltor crystals of the acid addition salt of the compound represented byFormula (I) or the pharmaceutical composition containing them of thepresent invention can be combined with another anticancer agent or thelike. For example, the acid addition salt or crystals of the acidaddition salt of the compound represented by Formula (I) or thepharmaceutical composition containing them of the present invention canalso be used in combination, or as a mixture, with another anticanceragent. Examples include trastuzumab, microtubule inhibitors[vinorelbine, taxane-based pharmaceutical agents (such as paclitaxel anddocetaxel), irinotecan, eribulin mesylate], platinum-basedpharmaceutical agents (such as cisplatin, carboplatin, oxaliplatin, andnedaplatin), 5-FU-based pharmaceutical agents (such as capecitabine and5-fluorouracil), breast cancer hormone therapies, HER2 inhibitors(trastuzumab, pertuzumab, lapatinib tosylate hydrate, neratinib,margetuximab), HER2 antibody conjugate drugs (trastuzumab emtansine(T-DM1), MM-302), IIDAC inhibitors (entinostat), PARP inhibitors(talazoparib, niraparib, olaparib, veliparib), immunotherapeuticvaccines (such as nelipepimut-S), CDK4/6 inhibitors (ibrance,ribociclib, abemaciclib), PI3K/mTOR inhibitors (buparlisib, taselisib,everolimus, alpelisib), immune checkpoint inhibitors (such as PD1/PD-L1inhibitors (nivolumab, atezolizumab, pembrolizumab), and the like. Also,two or more of the above anticancer agents can be used in combination.

The dosage of the acid addition salt or crystals of the acid additionsalt of the compound represented by Formula (I) of the present inventionalso varies according to the disease state, route of administration, ageof a patient, or body weight. The dosage is usually 10 to 1600mg/person/day, preferably 100 to 1200 mg/person/day, and most preferably200 to 800 mg/person/day in the case of oral administration to an adult.

The present invention is described in more detail by way of thefollowing Examples and Reference Examples. These do not limit thepresent invention. Concerning numerical values (for example, quantity,temperature, etc.), some errors and deviations should be taken intoconsideration.

Unless otherwise indicated, % is the weight % of a component and isbased on the total weight of a composition, and the pressure isatmospheric pressure or a pressure in the vicinity thereof.

Terms used herein are explained below:

g: gram

L: liter

mg: milligram

mL: milliliter

Boc: tert-butoxycarbonyl

(X-Ray Powder Diffraction Pattern Measurement)

Data of X-ray powder diffraction measurement of the obtained crystals ineach Example is obtained according to X-ray powder diffraction analysismethod in General tests in Japanese Pharmacopoeia as followingconditions.

(Method A)

(Device)

D-8 Discover by Bruker

(Operation method)

Samples were measured under the following conditions.

Measuring method: Reflection method

Light source: Cu tube

Wavelength used: CuKα ray

Tube current: 40 mA

Tube voltage: 40 kV

Sampling plate: Glass, aluminum

X-ray incident angle: 3-40

(Method B)

(Device)

MiniFlex 600 by Rigaku

(Operation method)

Samples were measured under the following conditions.

Measuring method: Reflection method

Light source: Cu tube

Used Wavelength: CuKα ray

Tube current: 15 mA

Tube voltage: 40 kV

Sampling plate: Circular, non-reflective sampling plate

X-ray incident angle: 4-40°

(DSC Measurement)

About 1 mg of the crystals obtained in each Example were weighed,stuffed in a high pressure pan made of gold-plated steal and measuredunder sealed system. The measurement conditions were as follows.

(Measurement Conditions)

Device: DSC Discovery by TA Instruments

Measurement temperature range: 25° C.-250° C.

Rate of temperature increase: 10° C./min

(TG/DTA Measurement)

About 10 mg of the crystals obtained in each Example was weighed,stuffed in aluminum pan and measured under open system. The measurementconditions were as follows.

(Measurement Conditions)

Device: TG/DTA 6300 by Hitachi High-Tech Science

Measurement temperature range: 30° C.-300° C.

Rate of temperature increase: 10° C./min

(NMR Measurement)

In NMR data shown in Examples and Reference Examples, not all measuredpeaks may be described.

(HPLC Measurement)

(Method A)

Device: Agilent 1290 Infinity

Detection wavelength: 232 nm

Column: ZORBAX SB-C18, 1.8 μm (2.1 mm×30 mm)

Column temperature: around 60° C.

Mobile phase: 0.1% aqueous trifluoroacetic acid solution/acetonitrilemixed solution (gradient from 90:10 to 10:90)

Flow rate: 1.2 mL/min

Injection amount: 1 μL

(Method B)

Device: Shimadzu 2010 Series or Shimadzu 10A VP Series

Column: CAPCELL PAK C18 MGII 3 μm Inner diameter 4.6 mm Length 150 mm

Mobile phase: [A] 10 mM aqueous ammonium acetate solution/[B]acetonitrile-methanol mixed solution (1:1)

Gradient program is shown in Table 1.

TABLE 1 Time after injection (min) Mobile phase A Mobile phase B  0 to40 40 60 40 to 60 40→10 60→90 60 to 70 10 90Flow rate: 1.0 mL/minDetection wavelength: 225 nmInjection amount: 10 μLColumn temperature: 35° C.(Moisture Sorption-Desorption Isothermal Measurement)

Moisture sorption-desorption isothermal measurement was performed on thecrystals obtained in each Example. About 10 mg of a sample was weighedonto a sample pan, and measurement was performed. Measurement conditionsare as shown below.

Device: DVS Advantage by Surface Measurement Systems Ltd.

Measurement points: from 0% Target % P/P₀ to 95% Target % P/P₀ inincrements of 5%, then from 95% Target % P/P₀ to 0% Target % P/P₀ indecrements of 5% Temperature: 25° C.

(Photostability Measurement)

A photostability test was performed using a photostability tester (modelLTL200A5-15WCD) by Nagano Science. A D65 lamp was used as an irradiationsource of light, and light was irradiated to a total illuminance ofabout 1.2 million 1×·hr under 4000 lx·hr conditions.

(Reference Example 1) Synthesis of Free Base A of Compound (I)

Compound 4 (8.23 g, 18.5 mmol) and Compound 3 (6.43 g, 27.7 mmol) weresuspended in dioxane (326 mL), and a 2 mol/L solution (23.3 mL) ofmethanesulfonic acid in methanol was added. The mixture was stirred at60° C. for 4 hours, then another portion of 2 mol/L methanesulfonic acid(14.1 mL) in methanol was added, and the mixture was stirred at 60° C.for 17 hours. The reaction solution was diluted with ethyl acetate (815mL) and water (200 mL), and an aqueous potassium carbonate solution(20.65 g of potassium carbonate, 150 mL of water) was added forextraction. The organic layer was washed with saline (50 mL of brine,250 mL of water). Then, the organic layer was dried over magnesiumsulfate and filtered, then the filtrate was concentrated, and thus freebase A (11.83 g) of Compound (I) was obtained as brown oil.

(Reference Example 2) Synthesis of Free Base B of Compound (I)

Free base A (6.88 g) synthesized using Compound 4 (4.94 g) according tothe synthesis method of Reference Example 1 was dissolved in methanol(28 mL), and a 4 mol/L solution (2.5 mL) of hydrochloric acid in ethylacetate was added. Stirring the mixture at room temperature for 2 hoursyielded precipitates. The mixture was diluted with ethyl acetate (50mL), and methanol was distilled off under reduced pressure. Thisoperation was repeated, and the mixture was further diluted with ethylacetate (30 mL) and stirred at room temperature for 30 minutes. Theresulting solids were filtered, washed with ethyl acetate (30 mL), anddried, and thus monohydrochloride (5.04 g) of Compound (I) was obtained.Then, 3.00 g of the monohydrochloride was suspended in ethyl acetate (50mL), an aqueous potassium carbonate solution (1.04 g of potassiumcarbonate, 15 mL of water) was added at 0° C., and the mixture wasextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous sodium sulfate, and filtered, and then the filtrate wasconcentrated under reduced pressure. Diethyl ether (24 mL) and hexane (6mL) were added to the residue, the resulting solids were washed with amixed solution of hexane:diethyl ether (1:1), and thus free base B (2.63g) of Compound (I) was obtained as pale yellow solids.

Example 1

Synthesis of Monohydrochloride Crystal Form I of Compound (I)

After free base A (1.18 g) of Compound (I) was dissolved in ethylacetate (8 mL) and filtered, the filtrate was concentrated under reducedpressure to a half volume, and a 4 mol/L solution (0.42 mL) ofhydrochloric acid in ethyl acetate was added. Diethyl ether (2 mL) wasadded, and the resulting precipitates were filtered and washed with amixed solution of diethyl ether:ethyl acetate (2:3) and then diethylether. Solids (817 mg) collected by filtration were dissolved inmethanol (20 mL) under warming, concentrated under reduced pressure to atotal amount of 3.6 g, and left to stand at room temperature.Precipitates were filtered, washed with cold methanol and then diethylether and dried, and thus monohydrochloride crystal Form I (701 mg) ofCompound (I) was obtained as yellow crystals.

¹H-NMR (300 MHz, DMSO-d6) δ 2.28 (6H, s), 3.08-3.28 (2H, m), 3.58-3.75(3H, m), 3.90-3.94 (1H, m), 4.03 (1H, dd, J=12, 2.7 Hz), 4.44 (2H, d,J=5.4 Hz), 5.27 (2H, s), 7.15-7.22 (1H, m), 7.26-7.35 (3H, m), 7.44-7.51(1H, m), 7.72 (1H, dd, J=9.0, 2.4 Hz), 7.82 (1H, d, J=8.7 Hz), 7.99 (1H,d, J=2.4 Hz), 8.26 (1H, dd, J=8.7, 1.8 Hz), 8.60 (1H, s), 8.88 (1H, d,J=1.5 Hz), 9.29 (1H, s), 10.20 (1H, s).

Elemental Analysis:

calculated value: C, 60.41; H, 4.73; Cl, 11.89; F, 3.19; N, 11.74.

measured value: C, 60.17; H, 4.79; Cl, 11.62; F, 3.06; N, 11.81.

The results of X-ray powder diffraction are shown in FIG. 1 and Table 2.

(Measurement Conditions: Method A)

TABLE 2 2θ 6.838 7.982 14.122 17.941 18.451 20.569 20.989 22.528 25.84328.409

Diffraction angles of major peaks (2θ) in X-ray powder diffractionspectrum: 8.0°±0.2°, 14.1°±0.2°, 20.6°±0.2°, 21.0°±0.2°, 25.8°±0.2°.

The results of TG/DTA measurement are shown in FIG. 4. The observedonset temperature was about 234° C. The weight loss of about 0.91% wasobserved on TG.

The results of DSC measurement are shown in FIG. 7. The observed onsettemperature was about 239° C.

The results of moisture sorption-desorption isothermal measurement areshown in FIG. 45. In the moisture sorption isothermal measurement, theratio of the increased mass at 95% Target % P/P₀ to the mass at 0%Target % P/P₀ was about 0.8. In the moisture desorption isothermalmeasurement, the ratio at 0% Target % P/P₀ was about 0.08.

Example 2 Synthesis of Monohydrochloride Crystal Form V of Compound (I)

2-Propanol (5.0 mL) was added to free base B (500 mg) of Compound (I),and the mixture was dissolved under warming at 65° C. After cooling, a 4mol/L solution (212 μL) of hydrochloric acid in ethyl acetate was added.The mixture was stirred at room temperature for 5 minutes andconcentrated under reduced pressure to a total amount of 3.09 g. Theresulting precipitates were filtered and washed with cold 2-propanol (3mL). The obtained solids were dissolved in methanol (13 mL) underwarming, and concentrated under reduced pressure to a total amount of3.03 g. The solution was diluted with ethyl acetate (6.0 mL) and againconcentrated under reduced pressure to a total amount of 2.84 g.Precipitates were collected by filtration, washed with cold ethylacetate (5 mL), and dried, and thus monohydrochloride crystal Form V(382 mg) of Compound (I) was obtained as yellow crystals.

The results of X-ray powder diffraction are shown in FIG. 2 and Table 3.

(Measurement Conditions: Method A)

TABLE 3 2θ 7.906 9.734 11.933 15.791 18.532 23.919 25.912 26.208 26.72828.399

Diffraction angles of major peaks (2θ) in X-ray powder diffractionspectrum: 23.9°±0.2°, 25.9°±0.2°, 26.2°±0.2°, 26.7°±0.2°, 28.4°±0.2°.

The results of TG/DTA measurement are shown in FIG. 5. The observedonset temperature was about 238° C. The weight loss of about 1.34% wasobserved on TG.

The results of DSC measurement are shown in FIG. 8. The observed onsettemperature was about 234° C.

The results of the moisture sorption-desorption isothermal measurementare shown in FIG. 46. In the moisture sorption isothermal measurement,the ratio of the increased mass at 95% Target % P/P₀ to the mass at 0%Target % P/P₀ was about 1.7. In the moisture desorption isothermalmeasurement, the ratio at 0% Target % P/P₀ was about 0.05.

Example 3

Synthesis of Monohydrochloride Crystal Form VI of Compound (I)

Free base A (1.00 g) of Compound (I) was dissolved in 2-propanol (8.0mL), then a 4 mol/L solution (318 μL) of hydrochloric acid in ethylacetate was added, and the mixture was stirred at room temperature for 1hour and at 0° C. for 1 hour. The mixture was stirred at roomtemperature for 30 minutes, and then precipitates were collected byfiltration. The precipitates were washed with 2-propanol and dried, andthus monohydrochloride crystal Form VI (592 mg) of Compound (I) wasobtained as pale yellow crystals.

The results of X-ray powder diffraction are shown in FIG. 3 and Table 4.

(Measurement Conditions: Method A)

TABLE 4 2θ 5.416 8.867 11.707 13.752 16.253 20.854 21.61 23.187 23.71826.616

Diffraction angles of major peaks (2θ) in X-ray powder diffractionspectrum: 5.4°±0.2°, 16.3°±0.2°, 21.6°±0.2°, 23.2°±0.2°, 23.7°±0.2°.

The results of TG/DTA measurement are shown in FIG. 6. The observedonset temperature was about 225° C. The weight loss of about 0.98% wasobserved on TG.

The results of DSC measurement are shown in FIG. 9. The observed onsettemperature was about 225° C.

The results of the moisture sorption-desorption isothermal measurementare shown in FIG. 47. In the moisture sorption isothermal measurement,the ratio of the increased mass at 95% Target % P/P₀ to the mass at 0%Target % P/P₀ was about 0.5. In the moisture desorption isothermalmeasurement, the ratio at 0% Target % P/P₀ was about 0.06.

Example 4

Synthesis of Monohydrochloride Crystal Form II of Compound (I)

Free base A (50.0 mg) of Compound (I) was dissolved in methanol (100 μL)and ethyl acetate (100 μL), and a 4 mol/L solution (21.2 μL) ofhydrochloric acid in ethyl acetate was added. The mixture was stirred atroom temperature for 1 hour and then diluted with ethyl acetate (500μL), and precipitates were collected by filtration. The precipitateswere washed with ethyl acetate (500 μL) and dried, and thusmonohydrochloride crystal Form II (14.4 mg) of Compound (I) was obtainedas colorless crystals.

The results of X-ray powder diffraction are shown in FIG. 12 and Table5.

(Measurement Conditions: Method A)

TABLE 5 2 θ 5.267 11.278 17.07 18.797 21.665 23.196 25.485 25.774 26.44729.391

Diffraction angles of major peaks (2θ) in X-ray powder diffractionspectrum: 11.3°±0.2°, 17.1°±0.2°, 25.5°±0.2°, 25.8°±0.2°, 26.4°±0.2°.

The results of TG/DTA measurement are shown in FIG. 25. The observedonset temperature was about 210.9° C. No weight loss was observed on TG.

The results of the moisture sorption-desorption isothermal measurementare shown in FIG. 48. In the moisture sorption isothermal measurement,the ratio of the increased mass at 95% Target % P/P₀ to the mass at 0%Target % P/P₀ was about 0.3. In the moisture desorption isothermalmeasurement, the ratio at 0% Target % P/P₀ was about 0.05.

Example 5

Synthesis of Monohydrochloride Crystal Form III of Compound (I)

Free base A (50.0 mg) of Compound (I) was dissolved in methanol (50 μL)and ethyl acetate (2θ0 μL), and a 4 mol/L solution (21.2 μL) ofhydrochloric acid in ethyl acetate was added. Solids were precipitatedimmediately thereafter. The mixture was diluted with ethyl acetate (300μL), and precipitates were collected by filtration. The precipitateswere washed with ethyl acetate (500 μL) and dried, and thusmonohydrochloride crystal Form III (25.0 mg) of Compound (I) wasobtained as pale yellow crystals.

The results of X-ray powder diffraction are shown in FIG. 13 and Table6.

(Measurement Conditions: Method A)

TABLE 6 2 θ 5.122 5.598 9.224 9.88 14.358 15.33 21.449 22.573 23.332

Diffraction angles of major peaks (2θ) in X-ray powder diffractionspectrum: 5.1°±0.2°, 9.9°±0.2°, 15.3°±0.2°, 21.4°±0.2°, 23.3°±0.2°.

The results of TG/DTA measurement are shown in FIG. 26. The observedonset temperature was about 223.9° C. No weight loss was observed on TG.

Example 6

Synthesis of Monohydrochloride Crystal Form VII of Compound (I)

1,2-Dimethoxyethane (2 mL) was added to monohydrochloride crystal FormVI (10 mg) of Compound (I), the crystal was dissolved under warming, andthen cooled with liquid nitrogen, the resulting precipitates werefiltered, and thus monohydrochloride crystal Form VII of Compound (I)was obtained as yellow crystals.

The results of X-ray powder diffraction are shown in FIG. 14 and Table7.

(Measurement Conditions: Method A)

TABLE 7 2 θ 5.686 7.008 11.386 12.328 15.95 17.327 19.1 21.234 22.969

Diffraction angles of major peaks (2θ) in X-ray powder diffractionspectrum: 7.0°±0.2°, 12.3°±0.2°, 16.0°±0.2°, 19.1°±0.2°, 21.2°±0.2°.

The results of TG/DTA measurement are shown in FIG. 27. The observedonset temperature was about 171.7° C. The weight loss of about 0.31% wasobserved on TG.

Example 7

Synthesis of Monohydrochloride Ethanolate Crystals of Compound (I)

Compound (IIA) (35.27 g, 74.0 mmol), p-toluenesulfonic acid monohydrate(13.41 g, 80.7 mmol), tetrahydrofuran (150 mL), and water (13 mL) weremixed, then Compound 4 (30.00 g, 67.3 mmol) was added, and stirred for 5hours at 50° C. After being cooled to room temperature, the mixture wasconcentrated to 126.8 g, the pH was adjusted to 9.5 with an aqueoussodium hydroxide solution, and the mixture was extracted with ethylacetate (240 mL×2). The extract was concentrated to 81.5 g, ethylacetate (240 mL) was added, and the mixture was again concentrated to79.7 g. Moreover, ethyl acetate (240 mL) was added, the mixture wasconcentrated to 61.6 g, and ethanol (240 mL) was added. The mixture washeated to 60° C., and monohydrochloride crystal Form I (9 mg) obtainedin Example 1 was added as seed crystals, then 5.83 mL of concentratedhydrochloric acid was added to precipitate solids. The mixture wasstirred at 25° C. for 2 hours and filtered, and thus monohydrochlorideethanolate crystals (36.31 g, 87.8%) of Compound (I) which is differentfrom the seed crystals were obtained.

The results of X-ray powder diffraction are shown in FIG. 15 and Table8.

(Measurement Conditions: Method A)

TABLE 8 2 θ 7.629 8.33 8.909 12.889 13.688 14.716 21.133 21.451 22.96523.709

Diffraction angles of major peaks (2θ) in X-ray powder diffractionspectrum: 8.3°±0.2°, 8.9°±0.2°, 12.9°±0.2°, 13.7°±0.2°, 14.7°±0.2°.

The results of TG/DTA measurement are shown in FIG. 28. The observedonset temperature was about 231° C. The weight loss of about 1.01% wasobserved on TG.

Example 8

Synthesis of Mono-p-Toluenesulfonate Crystal Form I of Compound (I)

Using Compound 4 (1.01 g) as a starting material, free base A (1.42 g)synthesized according to Reference Example 1 was purified by silica gelchromatography (chloroform:methanol=100:1 to 95:5), and the fraction ofthe target product was concentrated under reduced pressure. The residuewas dissolved in acetone and concentrated under reduced pressure, anddiethyl ether (4 mL) and hexane (1 mL) were added. The resulting solidswere filtered and washed with a mixed solution of hexane:diethyl ether(1:1) and hexane, and thus a free base (981 mg) was obtained. Then, 112mg of the free base was dissolved in ethyl acetate (1 mL), and a 1 mol/Lsolution (190 μL) of p-toluenesulfonic acid in methanol was added. Ethylacetate (2 mL) was added, and the mixture was stirred for 1 hour at roomtemperature. The resulting solids were collected by filtration, washedwith ethyl acetate and diethyl ether, and dried, and thusmono-p-toluenesulfonate crystal Form I (136 mg) of Compound (I) wasobtained as colorless crystals.

¹H-NMR (300 MHz, DMSO-d6) δ 2.29 (6H, s), 3.14-3.30 (2H, m), 3.52-3.81(3H, m), 3.88-3.89 (1H, m), 4.00-4.08 (1H, m), 4.41 (2H, d, J=5.5 Hz),5.28 (2H, s), 7.11 (2H, d, J=7.9 Hz), 7.15-7.24 (1H, m), 7.26-7.36 (3H,m), 7.45-7.52 (3H, m), 7.68 (1H, dd, J=8.8, 2.6 Hz), 7.83 (II, d, J=8.8Hz), 7.95 (II, d, J=2.5 Hz), 8.27 (II, dd, J=8.8, 1.7 Hz), 8.61 (1H, s),8.77 (1H, d, J=1.7 Hz), 8.90 (1H, s), 10.11 (1H, s).

Elemental Analysis:

calculated value: C, 60.69; H, 4.82; Cl, 4.84; F, 2.59; N, 9.56; S,4.38.

measured value: C, 60.45; H, 4.79; Cl, 4.47; F, 2.42; N, 9.46; S, 4.11

The results of X-ray powder diffraction are shown in FIG. 18 and Table9.

(Measurement Conditions: Method A)

TABLE 9 2 θ 6.096 6.376 10.75 13.744 15.689 16.259 20.049 22.717 24.58725.347

Diffraction angles of major peaks (2θ) in X-ray powder diffractionspectrum: 13.7°±0.2°, 15.7°±0.2°, 20.0°±0.2°, 22.7°±0.2°, 25.3°±0.2°.

The results of TG/DTA measurement are shown in FIG. 31. The observedonset temperature was about 2θ8.5° C. No weight loss was observed on TG.

The results of the moisture sorption-desorption isothermal measurementare shown in FIG. 49. In the moisture sorption isothermal measurement,the ratio of the increased mass at 95% Target % P/P₀ to the mass at 0%Target % P/P₀ was about 1.4. In the moisture desorption isothermalmeasurement, the ratio at 0% Target % P/P₀ was about 0.12.

Example 9

Synthesis of Monosulfate Crystals of Compound (I)

Free base A (50.0 mg) of Compound (I) was dissolved in acetonitrile (400μL), and a 1 mol/L solution (84.8 μL) of sulfuric acid in methanol wasadded. Acetonitrile (1 mL) was added, the mixture was stirred at 0° C.,and the resulting solids were collected by filtration and washed withcold acetonitrile. Solids were dried, and yellow crystals (15.1 mg) wereobtained. These were used as seed crystals.

Free base A (100 mg) of Compound (I) was dissolved in acetonitrile (400μL), and a 1 mol/L solution (179 μL) of sulfuric acid in methanol and asmall amount of the seed crystals prepared above were added.Acetonitrile (1 mL) was added, and the mixture was stirred at 0° C. Theresulting solids were collected by filtration, washed with coldacetonitrile, and dried, and thus monosulfate crystals (47.9 mg) ofCompound (I) were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ 2.30 (311, s), 3.12-3.24 (1H, m), 3.24-3.32(1H, m), 3.62-3.90 (3H, m), 3.93 (1H, d, J=11.4 Hz), 4.05 (1H, d, J=11.4Hz), 4.49-4.52 (2H, m), 5.32 (2H, s), 7.16-7.22 (1H, m), 7.3°-7.39 (3H,m), 7.45-7.52 (1H, m), 7.65-7.70 (1H, m), 7.91 (1H, d, J=2.0 Hz), 8.00(1H, d, J=8.8 Hz), 8.47 (1H, d, J=8.8 Hz), 8.95 (1H, s), 9.28 (1H, s),9.53 (1H, s), 9.64 (1H, s), 12.11 (1H, s).

Elemental Analysis:

calculated value: C, 54.08; H, 4.66; Cl, 5.32; F, 2.85; N, 10.51; S,4.33 (0.9H₂SO₄ 1.0H₂O).

measured value: C, 54.11; H, 4.78; Cl, 5.68; F, 2.65; N, 10.06; S, 4.32.

The results of X-ray powder diffraction are shown in FIG. 19 and Table10.

(Measurement Conditions: Method A)

TABLE 10 2 θ 6.202 12.065 13.963 14.459 15.894 16.168 16.785 21.03222.889 26.89

Diffraction angles of major peaks (2θ) in X-ray powder diffractionspectrum: 6.2°±0.2°, 14.0°±0.2°, 14.5°±0.2°, 16.8°±0.2°, 22.9°±0.2°.

The results of TG/DTA measurement are shown in FIG. 32. The observedonset temperature was about 190.5° C. No weight loss was observed on TG.

The results of the moisture sorption-desorption isothermal measurementare shown in FIG. 50. In the moisture sorption isothermal measurement,the ratio of the increased mass at 95% Target % P/P₀ to the mass at 0%Target % P/P₀ was about 3.3. In the moisture desorption isothermalmeasurement, the ratio at 0% Target % P/P₀ was about 0.13.

Example 10

Synthesis of Monosulfate Monohydrate Crystals of Compound (I)

Trihydrate crystals (3 mg) of the free base of Compound (I) produced bythe method described in Reference Example 5 were dissolved in a mixedsolution (0.15 mL) of acetonitrile:2-propanol (1:1), 0.1 mol/L sulfuricacid (0.056 mL) was added, and then the mixture was concentrated underreduced pressure. A mixed solution (0.3 mL) of methanol:water (95:5) wasadded, the mixture was shaken at 15° C. for 1 hour and then concentratedunder reduced pressure, and thus monosulfate monohydrate crystals ofCompound (I) were obtained.

The results of X-ray powder diffraction are shown in FIG. 20 and Table11.

(Measurement Conditions: Method A)

TABLE 11 2 θ 5.01 7.365 9.937 10.127 13.789 14.659 16.986 21.401

Diffraction angles of major peaks (2θ) in X-ray powder diffractionspectrum: 5.0°±0.2°, 9.9°±0.2°, 13.8°±0.2°, 14.7°±0.2°, 17.0°±0.2°.

The results of TG/DTA measurement are shown in FIG. 33. The weight lossof about 4.49% was observed on TG.

Example 11

Synthesis of Monophosphate Crystals of Compound (I)

Trihydrate crystals (3 mg) of the free base of Compound (I) weredissolved in a mixed solution (0.15 mL) of acetonitrile:2-propanol(1:1), 0.1 mol/L phosphoric acid (0.056 mL) was added, and then themixture was concentrated under reduced pressure. A mixed solution (0.3mL) of ethanol:water (95:5) was added, the mixture was shaken at 15° C.for 1 hour and then concentrated under reduced pressure, and thusmonophosphate crystals of Compound (I) were obtained.

The results of X-ray powder diffraction are shown in FIG. 21 and Table12.

(Measurement Conditions: Method A)

TABLE 12 2 θ 5.139 6.205 6.688 9.829 12.294 13.315 16.566 21.091

Diffraction angles of major peaks (2θ) in X-ray powder diffractionspectrum: 5.1°±0.2°, 6.2°±0.2°, 6.7°±0.2°, 9.8°±0.2°, 12.3°±0.2°.

The results of TG/DTA measurement are shown in FIG. 34. The observedonset temperature was about 188.1° C. The weight loss of about 1.76% wasobserved on TG.

Example 12

Synthesis of Monophosphate Dihydrate Crystal Form I of Compound (I)

Trihydrate crystals (3 mg) of the free base of Compound (I) weredissolved in a mixed solution (0.15 mL) of acetonitrile:2-propanol(1:1), 0.1 mol/L of phosphoric acid (0.056 mL) was added, and then themixture was concentrated under reduced pressure. A mixed solution (0.3mL) of methanol:water (95:5) was added, the mixture was shaken at 15° C.for 1 hour and then concentrated under reduced pressure, and thusmonophosphate dihydrate crystal Form I of Compound (I) was obtained.

The results of X-ray powder diffraction are shown in FIG. 22 and Table13.

(Measurement Conditions: Method A)

TABLE 13 2 θ 5.071 6.518 9.625 10.047 11.934 12.177 12.937 16.866 18.625

Diffraction angles of major peaks (2θ) in X-ray powder diffractionspectrum: 5.1°±0.2°, 6.5°±0.2°, 9.6°±0.2°, 12.9°±0.2°, 18.6°±0.2°.

The results of TG/DTA measurement are shown in FIG. 35. No weight losswas observed on TG.

Example 13

Synthesis of Monofumarate Crystal Form I of Compound (I)

Trihydrate crystals (3 mg) of the free base of Compound (I) weredissolved in a mixed solution (0.15 mL) of acetonitrile:2-propanol(1:1), a 0.1 mol/L solution (0.056 mL) of fumaric acid in methanol:water(1:1) was added, and then the mixture was concentrated under reducedpressure. A mixed solution (0.3 mL) of methanol:water (95:5) was added,the mixture was shaken at 15° C. for 1 hour and then concentrated underreduced pressure, and thus monofumarate crystal Form I of Compound (I)was obtained.

The results of X-ray powder diffraction are shown in FIG. 23 and Table14.

(Measurement Conditions: Method A)

TABLE 14 2 θ 5.443 5.971 7.984 9.058 10.043 12.306 14.752 16.131 19.51119.864

Diffraction angles of major peaks (2θ) in X-ray powder diffractionspectrum: 8.0°±0.2°, 9.1°±0.2°, 16.1°±0.2°, 19.5°±0.2°, 19.9°±0.2°.

The results of TG/DTA measurement are shown in FIG. 36. The observedonset temperature was about 191.3° C. No weight loss was observed on TG.

Example 14

Synthesis of Monofumarate Crystal Form II of Compound (I)

Trihydrate crystals (3 mg) of the free base of Compound (I) weredissolved in a mixed solution (0.15 mL) of acetonitrile:2-propanol(1:1), a 0.1 mol/L solution (0.056 mL) of fumaric acid in methanol:water(1:1) was added, and then the mixture was concentrated under reducedpressure. A mixed solution (0.3 mL) of acetonitrile:water (95:5) wasadded, the mixture was shaken at 15° C. for 1 hour and then concentratedunder reduced pressure, and thus monofumarate crystal Form II ofCompound (I) was obtained.

The results of X-ray powder diffraction are shown in FIG. 24 and Table15.

(Measurement Conditions: Method A)

TABLE 15 2 θ 5.444 8.031 9.065 13.304 13.717 16.429 17.112 18.051 19.88621.834

Diffraction angles of major peaks (2θ) in X-ray powder diffractionspectrum: 5.4°±0.2°, 9.1°±0.2°, 13.3°±0.2°, 13.7°±0.2°, 18.1°±0.2°.

The results of TG/DTA measurement are shown in FIG. 37. The observedonset temperature was about 195.6° C. The weight loss of about 1.42% wasobserved on TG.

(Reference Example 3) Synthesis of Free Base Crystals of Compound (I)

Free base B (50.0 mg) of Compound (I) was suspended in hexane (1 mL) andethyl acetate (0.7 mL) and dissolved under warming. The mixture was leftto stand at room temperature, then the resulting solids were collectedby filtration and dried, and thus free base crystals (39.9 mg) ofFormula (I) were obtained as colorless crystals.

¹H-NMR (400 MHz, DMSO-d6) δ 2.28 (3H, s), 2.74-2.83 (2H, m), 3.09-3.30(3H, m), 3.68 (1H, d, J=10.6 Hz), 3.82 (1H, d, J=10.6 Hz), 4.10-4.22(2H, m), 5.28 (2H, s), 7.19 (1H, t, J=8.2 Hz), 7.25-7.38 (3H, m),7.45-7.52 (1H, m), 7.71 (1H, d, J=8.8 Hz), 7.81 (1H, d, J=8.8 Hz), 7.99(1H, s), 8.22 (1H, d, J=8.8 Hz), 8.61 (1H, s), 8.76 (1H, s).

The results of X-ray powder diffraction are shown in FIG. 44 and Table16.

(Measurement Conditions: Method A)

TABLE 16 2 θ 5.428 13.891 16.224 17.18 19.513 20.383 23.334 23.62824.939 28.012

Diffraction angles of major peaks (2θ) in x-ray powder diffractionspectrum: 5.4°±0.2°, 13.9°±0.2°, 17.2°±0.2°, 20.4°±0.2°, 24.9°±0.2°.

The results of TG/DTA measurement are shown in FIG. 51. The observedonset temperature was about 134.1° C. No weight loss was observed on TG.

The results of the moisture sorption-desorption isothermal measurementare shown in FIG. 52. In the moisture sorption isothermal measurement,the ratio of the increased mass at 95% Target % P/P₀ to the mass at 0%Target % P/P₀ was about 1.0. In the moisture desorption isothermalmeasurement, the ratio at 0% Target % P/P₀ was about 0.16.

(Reference Example 4) Synthesis of Monohydrate Crystals of Free Base ofCompound (I)

Seed crystals of Free base of Compound (I) were added to the ethylacetate extract of Example 25 while being stirred at 15° C. until thecrystals did not dissolve any more. Large amounts of precipitatedcrystals were collected by filtration, and thus monohydrate crystals ofthe free base of Compound (I) were obtained.

Moisture value: 30.23% (Theoretical value of monohydrate: 3.12%)

The results of X-ray powder diffraction are shown in FIG. 16 and Table17.

(Measurement Conditions: Method A)

TABLE 17 2 θ 6.045 8.307 11.758 12.097 16.61 20.056 25.487 26.087 27.368

Diffraction angles of major peaks (2θ) in X-ray powder diffractionspectrum: 6.0°±0.2°, 8.3°±0.2°, 20.1°±0.2°, 25.5°±0.2°, 26.1°±0.2°.

The results of TG/DTA measurement are shown in FIG. 29. The weight lossof about 20.27% was observed on TG.

(Reference Example 5) Synthesis of Trihydrate Crystals of Free Base ofCompound (I)

Crystals precipitated when concentrating the extract of Example 25 werecollected by filtration and subjected to through-flow drying, and thustrihydrate crystals of the free base of Compound (I) were obtained.

Moisture value: 9.87% (Theoretical value of trihydrate: 8.8%)

The results of X-ray powder diffraction are shown in FIG. 17 and Table18.

(Measurement Conditions: Method A)

TABLE 18 2 θ 5.919 8.735 10.92 11.742 13.811 21.249 23.55 24.689 25.427.297

Diffraction angles of major peaks (2θ) in X-ray powder diffractionspectrum: 5.9°±0.2°, 8.7°±0.2°, 10.9°±0.2°, 24.7°±0.2°, 25.4%° 0.2°.

The results of TG/DTA measurement are shown in FIG. 30. The weight lossof about 11.2% was observed on TG.

(Reference Example 6) Synthesis of Dihydrochloride Crystals of Compound(I)

First, to 16 g of the ethanol solution (about 400 g) containing the freebase (about 50 g) of Compound (I), the monohydrochloride crystal Form 1(2.5 mg) obtained in Example 1 was added, and then 0.838 g (2.5 eq) ofconcentrated hydrochloric acid was added. The mixture was stirred for 2hours, then the precipitated solids were collected by filtration, andthus dihydrochloride crystals of Compound (I) were obtained.

Elemental Analysis:

calculated value: C, 57.59; H, 4.64; Cl, 15.87; F, 3.04; N, 11.19(1.8HCl salt).

measured value: C, 57.99; H, 5.51; Cl, 16.74; F, 2.86; N, 11.47.

The results of X-ray powder diffraction are shown in FIG. 38.(Measurement conditions: Method A)

(Reference Example 7) Synthesis of Mono-p-Toluenesulfonate Crystal FormII of Compound (I)

Free base A (50.0 mg) of Compound (I) was dissolved in acetonitrile (500μL), and a 1 mol/L solution (84.8 μL) of p-toluenesulfonic acid inmethanol was added. The mixture was stirred at room temperature for 2hours, acetonitrile (500 μL) was added, the mixture was further stirredfor 1 hour and diluted with ethyl acetate, and the resulting solids werecollected by filtration. The solids were dried, and thusmono-p-toluenesulfonate crystal Form II (29.7 mg) of Compound (I) wasobtained as colorless crystals.

The results of X-ray powder diffraction are shown in FIG. 39.(Measurement conditions: Method A)

(Reference Example 8) Synthesis of Monobenzenesulfonate Crystals ofCompound (I)

Trihydrate crystals (3 mg) of the free base of Compound (I) weredissolved in a mixed solution (0.15 mL) of acetonitrile:2-propanol(1:1), a 0.1 mol/L aqueous solution (0.056 mL) of benzenesulfonic acidwas added, and then the mixture was concentrated under reduced pressure.A mixed solution (0.3 mL) of methanol:water (95:5) was added, themixture was shaken at 15° C. for 1 hour and then concentrated underreduced pressure, and thus monobenzenesulfonate crystals of Compound (I)were obtained.

The results of X-ray powder diffraction are shown in FIG. 40.(Measurement conditions: Method A)

(Reference Example 9) Synthesis of Monophosphate Dihydrate Crystal FormII of Compound (I)

Trihydrate crystals (3 mg) of the free base of Compound (I) weredissolved in a mixed solution (0.15 mL) of acetonitrile:2-propanol(1:1), 0.1 mol/L phosphoric acid (0.056 mL) was added, and then themixture was concentrated under reduced pressure. A mixed solution (0.3mL) of methyl acetate:water (95:5) was added, the mixture was shaken at15° C. for 1 hour and then concentrated under reduced pressure, and thusmonophosphate dihydrate crystal Form II of Compound (I) was obtained.

The results of X-ray powder diffraction are shown in FIG. 41.(Measurement conditions: Method A)

(Reference Example 10) Synthesis of Monocitrate Crystals of Compound (I)

Trihydrate crystals (3 mg) of the free base of Compound (I) weredissolved in a mixed solution (0.15 mL) of acetonitrile:2-propanol(1:1), a 0.1 mol/L aqueous solution (0.056 mL) of citric acid was added,and then the mixture was concentrated under reduced pressure. A mixedsolution (0.3 mL) of methanol:water (95:5) was added, the mixture wasshaken at 15° C. for 1 hour and then concentrated under reducedpressure, and thus monocitrate crystals of Compound (I) were obtained.

The results of X-ray powder diffraction are shown in FIG. 42.(Measurement conditions: Method A)

(Reference Example 11) Synthesis of Monotartrate Crystals of Compound(I)

Trihydrate crystals (3 mg) of the free base of Compound (I) weredissolved in a mixed solution (0.15 mL) of acetonitrile:2-propanol(1:1), a 0.1 mol/L aqueous solution (0.056 mL) of tartaric acid wasadded, and then the mixture was concentrated under reduced pressure. Amixed solution (0.3 mL) of methanol:water (95:5) was added, the mixturewas shaken at 15° C. for 1 hour and then concentrated under reducedpressure, and thus monotartrate crystals of Compound (I) were obtained.

The results of X-ray powder diffraction are shown in FIG. 43.(Measurement conditions: Method A)

Example 15

(Results of XRPD Measurement) A compound having a structure similar tothat of Compound (I) of the present application is disclosed as Compound(VI-1) in Example 2 of Patent Document 2. Compound (VI-1) is describedas being obtained as dihydrochloride crystals.[Chemical Formula 24]

Next, the pKa values of nitrogen atoms having basicity of the free basesof Compound (VI-1) described in Patent Document 2 and Compound (I)described in the present application are shown. In order to calculatethe pKa values, ACD/Labs (Technical Computing Solution ACD/Labs, byFujitsu) was used.

As is clear from above, the respective pKa values of the basic nitrogenatoms of the morpholine moieties and the basic nitrogen atoms of thequinazoline moieties show nearly the same values.

Generally, it is said that a salt can be formed when the differencebetween the pKa values of a base and a counter (for example,hydrochloric acid) is 3 or greater. Since hydrochloric acid has a pKavalue of −6, the free base of Compound (I) described in the presentapplication can also form dihydrochloride (References: Recent Progressin Physicochemical Characterization and Formulation Technologies forPoorly Soluble Drugs, 2010, pp. 111-121; Structure, solubility,screening, and synthesis of molecular salts, JOURNAL OF PHARMACEUTICALSCIENCES, VOL. 96, NO. 5, May 2007).

Here, dihydrochloride crystals of Compound (I) prepared according toReference Example 6 exhibited a broad peak as shown in FIG. 38, and itwas thus found that dihydrochloride crystals of Compound (I) have lowcrystallinity.

In general, low crystallinity crystals are known to have poor physicalstability, poor chemical stability, and such features, and it is saidthat the handling of such an active pharmaceutical ingredient isdifficult (Reference: Recent Progress in PhysicochemicalCharacterization and Formulation Technologies for Poorly Soluble Drugs,2010, pp. 215-216). For example, in the case of using low crystallinitycrystals as an active ingredient, they may transition to crystals thathave good crystallinity when synthesis is carried out in a large scale.Also, due to poor stability, they are not suitable for long-termstorage.

Various crystals of monohydrochloride of Compound (I) described inExamples 1 to 7 are crystals having good crystallinity as shown in FIGS.1 to 3 and FIGS. 12 to 15, and it is an unexpected effect that formingCompound (I) into monohydrochloride provides crystal polymorphs suitablefor an active pharmaceutical ingredient.

Also, it was found that mono-p-toluenesulfonate crystal Form II,monobenzenesulfonate crystals, monophosphate dihydrate crystal Form II,monocitrate crystals, and monotartrate crystals of Compound (I)described in Reference Examples 7 to 11 exhibit broad peaks as shown inFIGS. 39 to 43 and have low crystallinity.

From above, it was found that only low crystallinity crystals wereobtained from not only dihydrochloride of Compound (I) but also some ofthe salts obtained by addition of one acid molecule but, on the otherhand, monohydrochloride crystals of Compound (I) in any crystal formhave good crystallinity and are in crystal forms suitable for use as anactive pharmaceutical ingredient of a drug.

Example 16

(Test of Solubility in Water for Injection)

1. Preparation of Calibration Curve

First, 5 mg of monohydrochloride crystal Form I of Compound (I) wasprecisely weighed and dissolved in a mixed solution ofacetonitrile:water (1:1), and thus a 500 μg/mL solution was obtained.The obtained solution was diluted with a mixed solution ofacetonitrile:water (1:1) such that the concentrations of the compoundwere 5 and 50 μg/mL. Accordingly, a standard calibration curve wasprepared according to HPLC measurement conditions (Method A). The sameoperation was carried out for monohydrochloride crystal Form II,monohydrochloride crystal Form V, monohydrochloride crystal Form VI,mono-p-toluenesulfonate crystal Form I, and free base crystals.

2. Preparation of Sample Solution

First, 1 mg of monohydrochloride crystal Form I of Compound (I) wasprecisely weighed and transferred to a vial having a volume of 4 mL.Then, 1 mL of water (water for injection) was added, and the mixture wasstirred at 37° C. for 1 hour. After being stirred, this suspension wasfiltered, and the peak area was measured under HPLC measurementconditions (Method A) using a solution obtained by diluting the filtratetwo-fold with a mixed solution of acetonitrile:water (1:1) as a sample.The concentration was calculated using the peak area and the calibrationcurve prepared above. The same operation was carried out formonohydrochloride crystal Form II, monohydrochloride crystal Form V,monohydrochloride crystal Form VI, mono-p-toluenesulfonate crystal FormI, and free base crystals.

(Results)

The respective solubilities of the monohydrochloride crystal Form 1,monohydrochloride crystal Form II, monohydrochloride crystal Form V,monohydrochloride crystal Form VI, mono-p-toluenesulfonate crystal FormI, and free base crystals of Compound (I) in water for injection areshown in Table 19.

TABLE 19 Monohydro- Monohydro- Monohydro- Monohydro- Mono-p- Free basechloride chloride chloride chloride toluenesulfonate crystal crystalForm I crystal Form II crystal Form V crystal Form VI crystal Form IWater for N.D. 34.5 56.0 14.0 12.9 26.6 injection (N.D.: Not Detected,Unit: μg/mL)

As is clear from the above table, the free base crystals of Compound (I)was not dissolved in water for injection at all but, on the other hand,the monohydrochloride crystal Form I, monohydrochloride crystal Form II,monohydrochloride crystal Form V, monohydrochloride crystal Form VI, andmono-p-toluenesulfonate crystal Form I of Compound (I) showed highsolubilities in water for injection.

In general, the solubility of a pharmaceutical agent is deeply involvedin disposition, and an active pharmaceutical ingredient is desired tohave high solubility. Accordingly, it was found that themonohydrochloride crystal Form I, monohydrochloride crystal Form II,monohydrochloride crystal Form V, monohydrochloride crystal Form VI, andmono-p-toluenesulfonate crystal Form I of Compound (I) have highsolubilities, and are in crystal forms suitable for use as an activepharmaceutical ingredient of a drug.

Example 17

(Test of Solubility in Organic Solvent)

The monohydrochloride crystal Form I, monohydrochloride crystal Form V,and free base crystals of Compound (I) were each suspended in2-propanol, acetone, and ethyl acetate, and stirred at 22° C. for 4hours, and the concentrations of supernatants were measured (HPLC:Method B).

(Results) Solubilities in 2-propanol, acetone, and ethyl acetate areshown in Table 20.

TABLE 20 Concentration (% by weight) Sample 2-Propanol Acetone Ethylacetate Monohydrochloride crystal Form I 0.03 0.08 0.01Monohydrochloride crystal Form V 0.01 0.02 0.00 Free base crystal 0.498.1 3.3

As is clear from Table 20, it can be understood that the concentrations(% by weight) of the free base crystals of Compound (I) in variousorganic solvents are high (about 0.5% by weight to about 8% by weight),showing high solubility, but, on the other hand, the monohydrochloridecrystal Form I and the monohydrochloride crystal Form V of Compound (I)barely dissolve in various organic solvents (both 0.1% by weight orless). That is to say, when synthesizing Compound (I) as described inReference Example 1 above or Example 18 or 25 below, if the producedCompound (I) has high solubility in organic solvents, the ratio of theproduct precipitated from organic solvents is small, and the yield isreduced. Accordingly, it was found that the monohydrochloride crystalForm I and the monohydrochloride crystal Form V of Compound (I) are incrystal forms suitable for use as an active pharmaceutical ingredient ofa drug.

Example 18

(Purification Effect by Crystallization)

Purification effects of the free base crystals, monohydrochloridecrystal Form I, and monohydrochloride crystal Form VI of Compound (I)crystallized from an ethyl acetate solution of Compound (I) werecompared respectively.

(Step 1) Synthesis of Ethyl Acetate Solution of Compound (I)

Compound 4 (30.04 g, 67.4 mmol) was dissolved in N-methylpyrrolidone(70.86 g) and tetrahydrofuran (18.68 g), added to a slurry of Compound(IIA) (36.85 g, 77.3 mmol), p-toluenesulfonic acid monohydrate (15.37 g,80.8 mmol), tetrahydrofuran (53.41 g), and water (5.40 g), and stirredat 57° C. for 5 hours. After the mixture was cooled to room temperature,Compound 4 (0.25 g) was added. Thereafter, the pH was adjusted to 9.0with an aqueous sodium hydroxide solution, followed by extraction withethyl acetate (651.52 g). The extract was concentrated to 107.39 g,ethyl acetate (162.40 g) was added, and thus an ethyl acetate solution(269.76 g) of Compound (I) was obtained.

(Step 2-1) Synthesis of Free Base Crystals of Compound (I)

The ethyl acetate solution (89.92 g) of Compound (I) was concentrated to22.97 g, heptane (17.67 g) and ethyl acetate (13.27 g) were added, thenthe mixture was heated to 60° C., and thus solids were precipitated.Ethyl acetate (12.31 g) was added, the mixture was cooled to roomtemperature, heptane (41.26 g) and ethyl acetate (6.0 g) were added, andthe mixture was concentrated to 49.70 g. Heptane (49.83 g) and ethylacetate (27.0 g) were added, the mixture was left to stand overnight andthen filtered, and thus free base crystals (10.91 g, 86.7%) of Compound(I) were obtained.

(Step 2-2) Synthesis of Monohydrochloride Crystal Form I of Compound (I)

Water (0.13 g) and 2-propanol (16.26 g) were added to the ethyl acetatesolution (40.72 g) of Compound (I), and the mixture was heated to 45° C.Seed crystals (225.7 mg) of crystal Form T was added, and then the pHwas adjusted to 4.07 with 35% hydrochloric acid. The mixture was stirredat 25° C. for about 30 minutes and then filtered, and thusmonohydrochloride crystal Form I (5.50 g, 90.6%) of Compound (I) wasobtained.

(Step 2-3) Synthesis of Monohydrochloride Crystal Form VI of Compound(I)

2-Propanol (7.85 g) was added to the ethyl acetate solution (45.20 g) ofCompound (I), and the mixture was heated to 60° C. The pH was adjustedto 3.5 with 35% hydrochloric acid, then the mixture was stirred at 25°C. for about 30 minutes and filtered, and thus monohydrochloride crystalForm VI (5.84 g, 86.7%) of Compound (I) was obtained.

The qualities of the free base crystals, monohydrochloride crystal FormI, and monohydrochloride crystal Form VI of Compound (I) obtained by theabove synthesis methods were evaluated using HPLC (HPLC: Method B).

TABLE 21 Retention time Impuri- Impuri- E Compound Impuri- ty A ty Bisomer (I) ty C Sample 20 min 21 min 38 min 44 min 62 minPre-crystallization 0.31 0.12 6.26 89.38 0.74 solution (Ethyl acetatesolution) Free base crystal 0.12 0.05 1.29 97.81 0.67 Monohydrochloride0.16 0.03 1.00 98.44 0.27 crystal Form I Monohydrochloride 0.02 N.D.0.80 99.17 N.D. crystal Form VI (N.D.: Not Detected, Unit: Area %)

When the purities of the respective crystals obtained above arecompared, as is clear from Table 21, it can be understood that in orderof monohydrochloride crystal Form VI, monohydrochloride crystal Form I,and free base crystals, the ratio of the peak area % of Compound (I) islarger (about 99.2%, about 98.4%, and about 97.8%, respectively), andthe amount of various impurities contained is smaller. Accordingly, itwas found that when performing crystallization from apre-crystallization solution (an ethyl acetate solution) containinglarge amounts of impurities, it is possible to remove various impuritiesand obtain crystals having a higher purity by obtaining crystals asmonohydrochloride crystal Form VI or monohydrochloride crystal Form Ithan obtaining crystals as free base crystals.

In general, for crystals containing large amounts of impurities, it isnecessary to repeat the recrystallization step to increase the purity ofthe crystals. When the recrystallization step is repeated, the amount ofcrystals elute into the mother liquor is increased, thus resulting in areduced yield. Depending on the impurity, the ratio of the impurityremoved by the recrystallization step is small, and therefore it isoften the case that the purity cannot be increased by repeating therecrystallization step a practical number of times.

Accordingly, it can be said that the monohydrochloride crystal Form VIand the monohydrochloride crystal Form I of Compound (I) are in crystalforms suitable for scale-up synthesis because high-purity crystals canbe obtained by single crystallization. That is to say, it was found thatthe monohydrochloride crystal Form VI and the monohydrochloride crystalForm I of Compound (I) are in crystal forms suitable for use as anactive pharmaceutical ingredient of a drug.

Example 19

(Water Sorption-Desorption Isothermal Measurement)

Table 22 shows the ratios of increased moisture mass of themonohydrochloride crystal Form I, monohydrochloride crystal Form V,monohydrochloride crystal Form VI, free base crystals,mono-p-toluenesulfonate crystals, and monosulfate crystals of Compound(I).

TABLE 22 Ratio of increased mass Monohydrochloride crystal Form I About0.8% Monohydrochloride crystal Form II About 0.3% Monohydrochloridecrystal Form V About 1.7% Monohydrochloride crystal Form VI About 0.5%Mono-p-toluenesulfonate crystal Form I About 1.4% Free base crystalAbout 1.0% Monosulfate crystal About 3.3%

As is clear from Table 22, it was found that the monosulfate crystals ofCompound (I) exhibited a moisture increase of about 3.3% but, on theother hand, the ratios of moisture increase of the monohydrochloridecrystal Form I, monohydrochloride crystal Form II, monohydrochloridecrystal Form V, monohydrochloride crystal Form VI, andmono-p-toluenesulfonate crystal Form I of compound (I) were small.

In general, it is considered that salt crystals are more likely to beinfluenced by moisture absorption, and absorptivity is said to varydepending on the type of salt (Reference: Recent Progress inPhysicochemical Characterization and Formulation Technologies for PoorlySoluble Drugs, 2010, pp. 117-118). Also, crystals that are likely toadsorb water undergo deliquescence and like a phenomenon, and it isdifficult to handle such crystals. Moreover, such crystals are notsuitable for long-term storage and are rarely selected as an activepharmaceutical ingredient. Accordingly, it was found that themonohydrochloride crystal Form I, monohydrochloride crystal Form II,monohydrochloride crystal Form V, monohydrochloride crystal Form VI, andmono-p-toluenesulfonate crystal Form I of Compound (I) are in crystalforms suitable for use as an active pharmaceutical ingredient of a drugbecause the ratios of moisture increase are small.

Example 20

(Light Exposure Test)

Table 23 shows the results of a light exposure test of themonohydrochloride crystal Form I, monohydrochloride crystal Form II,monohydrochloride crystal Form V, monohydrochloride crystal form VI, andmono-p-toluenesulfonate crystal Form I of Compound (I). The qualityevaluations of the respective crystals were carried out using HPLC(Method B).

TABLE 23 E isomer (Retention time 38 minutes)* Light Dark exposedIncreased Sample control sample amount Monohydrochloride crystal Form I0.63 4.41 3.78 Monohydrochloride crystal Form II 1.44 1.21 −0.23Monohydrochloride form crystal V 0.13 1.19 1.06 Monohydrochloride formcrystal VI 1.16 1.80 0.64 Free base crystal N.D. 2.59 2.59Mono-p-toluenesulfonate crystal 0.10 32.86 32.76 Form I (The unit isarea %. *Concerning other peaks, changes due to light exposure arebarely recognized.)

As shown in Table 23, when the monohydrochloride crystal Form I,monohydrochloride crystal Form II, monohydrochloride crystal Form V, andmonohydrochloride crystal Form VI of Compound (I) were subjected to alight exposure test, conversion from a Z isomer to an E isomer wasbarely observed, or an increase was only as much as about 3.8%. On theother hand, it was found that the photostability of themono-p-toluenesulfonate crystal Form I of Compound (I) is poor becausethe E isomer was increased about 33% after light exposure.

In general, crystals having poor photostability undergo decompositionand like a phenomenon due to light, and unacceptable changes may occurdue to light exposure. Also, such crystals require utmost attention tothe storage method, and it is difficult to handle such crystals.

Accordingly, it was found that the monohydrochloride crystal Form I,monohydrochloride crystal Form II, monohydrochloride crystal Form V, andmonohydrochloride crystal Form VI of Compound (I) are in crystal formssuitable for use as an active pharmaceutical ingredient of a drugbecause light stability under light exposure conditions is good.

Example 21

Synthesis of Compound (IIA)

Triphenylphosphine (20.3 g, 77.3 mmol), diisopropyl azodicarboxylate(16.6 g, 81.8 mmol), Compound 1 (14.0 g, 64.4 mmol), andN-hydroxyphthalimide (4.2 g, 70.9 mmol) were stirred at 5 to 15° C. for2 hours in tetrahydrofuran (98 mL) and toluene (77 ml), and thus apreparation solution for Compound 2 was obtained. A 35% aqueousmonomethylhydrazine solution (9.3 g, 70.9 mmol) was added thereto, themixture was stirred at 15° C. for 2 hours, and thus a preparationsolution for Compound 3 was obtained. The preparation solution forCompound 3 was concentrated to 114 g and stirred at 0° C. for 2 hours.Precipitated insoluble material was filtered, and toluene (56 mL) wasadded to the filtrate. This toluene solution was added to a solution ofp-toluenesulfonic acid monohydrate (28.2 g, 148.1 mmol) intetrahydrofuran (42 mL), and the mixture was stirred at 50° C. for 2hours. Moreover, the mixture was cooled to 0° C., stirred for 2 hours,and filtered, and thus compound (IIA) (27.2 g, yield 88.4%) wasobtained.

¹H-NMR (CD₃OD) δ: 7.67-7.73 (4H, m), 7.20-7.26 (4H, m), 4.92 (5H, bs),4.30-4.34 (2H, m), 3.91-4.03 (2H, m), 3.63-3.79 (3H, m), 3.18-3.38 (2H,m), 2.36 (6H, s).

The results of X-ray powder diffraction are shown in FIG. 10 and Table24.

(Measurement Conditions: Method A)

TABLE 24 2θ 6.396 7.256 11.427 15.232 17.646 20.135 21.05 21.748 24.7225.315

Diffraction angles of major peaks (2θ) in X-ray powder diffractionspectrum: 6.4°±0.2°, 7.3°±0.2°, 21.1°±0.2°, 24.7°±0.2°, 25.3°±0.2°.

Example 22

Compound (IIA) (31.2 mg) was left to stand in a high humidityenvironment, and thus dihydrate (33.8 mg) of Compound (IIA) wasobtained.

The results of X-ray powder diffraction are shown in FIG. 11 and Table25.

(Measurement Conditions: Method A)

TABLE 25 2θ 7.315 17.043 18.451 19.701 21.702 22.578 22.804 24.02424.776 29.691

Diffraction angles of major peaks (2θ) in X-ray powder diffractionspectrum: 7.3°±0.2°, 17.0°±0.2°, 18.5°±0.2°, 22.6°±0.2°, 24.0°±0.2°.

(Reference Example 12) Synthesis of Compound (II′)

Ethyl acetate (8 mL) was added to Compound 3 (4.12 g, 17.7 mmol), andthe mixture was stirred. When 4 mol/L a solution (16 mL) of hydrochloricacid in ethyl acetate was added, white solids were precipitated. Ethylacetate (8 mL) was added, and then the mixture was stirred for about 4hours at room temperature. Highly hygroscopic Compound (II′) werecollected by filtration.

¹H-NMR (DMSO-d6) δ: 9.60-11.50 (4H, bs), 4.20-4.31 (2H, m), 3.86-3.93(2H, m), 3.21-3.77 (4H, in), 3.01-3.10 (1H, in).

The obtained compound absorbed moisture and deliquesced, and thereforeit was not possible to perform measurements such as X-ray powderdiffraction.

(Reference Example 13) Synthesis of Compound (II″)

Benzenesulfonic acid (78.57 mg) and tetrahydrofuran (0.2 mL) werestirred at 50° C., and a tetrahydrofuran (0.2 mL) solution of Compound 3(51.54 mg, 0.222 mmol) was added dropwise. After about 20 minutes,cooling the mixture to room temperature caused solids to precipitate.Then, 0.15 mL of tetrahydrofuran was added, and the mixture was stirredat 50° C. for 10 minutes and cooled to 10° C. Solids were collected byfiltration in a nitrogen atmosphere, and thus 57.3 mg of highlyhygroscopic Compound (II″) was obtained.

¹H-NMR (CD3OD) δ: 7.84-7.87 (4H, m), 7.45-7.47 (6H, m), 4.34-4.36 (2H,m), 3.98-4.08 (2H, m), 3.71-3.80 (3H, m), 3.28-3.41 (2H, m).

The results of X-ray powder diffraction are shown in FIG. 53 and Table26.

(Measurement Condition: Method B)

TABLE 26 2θ 5.600 8.020 16.260 18.000 19.020 22.220 23.160 24.400 24.50025.520

Diffraction angles of major peaks (2θ) in X-ray powder diffractionspectrum: 5.6°±0.2°, 8.0°±0.2°, 18.0°±0.2°, 19.0°±0.2°, 24.5°±0.2°.

Example 23

(Results of XRPD Measurement)

The crystals of Compound (II′) described in Reference Example 12 havedeliquescing properties and have low crystallinity. Also, as shown inFIG. 53, the crystals of Compound (II″) described in Reference Example13 show low intensity peaks and have low crystallinity. As described inExample 15 above, it is difficult to handle low crystallinity crystals.On the other hand, it was found that the crystals of Compound (IIA) andthe dihydrate crystals of Compound (IIA) described in Examples 21 and 22are crystals having good crystallinity as shown in FIGS. 10 and 11, andare in crystal forms that can be selected as an intermediate of anactive pharmaceutical ingredient.

Example 24

(Results of Stability Test)

The crystals of Compound (IIA) obtained in Example 21 were heated at 50°C. for 8 hours and measured NMR data. As a result, compared with thepeaks before heating, no changes to the peaks were observed, and it wasthus found that the crystals of Compound (IIA) are highly stablecrystals.

Example 25

Synthesis of Monohydrochloride Crystal Form VI of Compound (I)

Compound 4 (97.01 g, 217.6 mmol) dissolved in N-methylpyrrolidone (223mL) and tetrahydrofuran (116 mL) was mixed with Compound (IIA) (119.25g, 250.2 mmol), p-toluenesulfonic acid monohydrate (49.67 g, 261.1mmol), tetrahydrofuran (194 mL), and water (17 mL), and the mixture wasstirred at 57° C. for 5 hours. After the mixture was cooled to roomtemperature, the pH was adjusted to 9.0 with an aqueous sodium hydroxidesolution, followed by extraction with ethyl acetate (776 mL). Theextract was concentrated to 357 mL, ethyl acetate (582 mL) was added,and thus 882.12 g of a dilution was obtained.

2-Propanol (10 mL) was added to 44.11 g of the dilution, and the mixturewas heated to 60° C. After the pH was adjusted to 4.3 with 35%hydrochloric acid, the mixture was stirred at 25° C. for 4 hours andfiltered, and thus monohydrochloride crystal Form VI (5.6 g, 86.8%) ofCompound (I) was obtained.

The following Formulation Examples are mere examples and do not intendto limit the scope of the invention in any way.

Formulation Example 1: Tablet

An acid addition salt or crystals of the acid addition salt of thecompound represented by Formula (I) of the present invention, lactose,and calcium stearate are mixed. The mixture is crushed, granulated, anddried to form granules having a suitable size. Next, calcium stearate isadded, and the mixture is compression-molded to form tablets.

Formulation Example 2: Capsule

An acid addition salt or crystals of the acid addition salt of thecompound represented by Formula (I) of the present invention, lactose,and calcium stearate are uniformly mixed to make a powdered drug in apowdery or fine granule form. Capsule shells are filled therewith toform capsules.

Formulation Example 3: Granule

An acid addition salt or crystals of the acid addition salt of thecompound represented by Formula (I) of the present invention, lactose,and calcium stearate are uniformly mixed. After beingcompression-molded, the mixture is pulverized, classified, and sieved toform granules having a suitable size.

Formulation Example 4: Orally Disintegrating Tablet

An acid addition salt or crystals of the acid addition salt of thecompound represented by Formula (I) of the present invention andcrystalline cellulose are mixed, granulated, and then tableted to formorally disintegrating tablets.

Formulation Example 5: Dry Syrup

An acid addition salt or crystals of the acid addition salt of thecompound represented by Formula (I) of the present invention and lactoseare mixed, pulverized, classified, and sieved to form a dry syrup havinga suitable size.

Formulation Example 6: Inhalant

An acid addition salt or crystals of the acid addition salt of thecompound represented by Formula (I) of the present invention and lactoseare mixed and finely pulverized to thereby form an inhalant.

INDUSTRIAL APPLICABILITY

Hydrochloride or crystals of the hydrochloride as well asmono-p-toluenesulfonate or crystals of the mono-p-toluenesulfonate ofthe compound represented by Formula (I), which are the presentinvention, are useful as active pharmaceutical ingredients. Also, apharmaceutical composition containing hydrochloride or crystals of thehydrochloride or mono-p-toluenesulfonate or crystals of themono-p-toluenesulfonate of the compound represented by Formula (I) isextremely useful as a therapeutic agent or a prophylactic agent forcancer.

In addition, the compound represented by Formula (II), apharmaceutically acceptable salt thereof, or their solvates are usefulintermediates when producing hydrochloride or crystals of thehydrochloride of the compound represented by Formula (I).

The invention claimed is:
 1. A pharmaceutical composition comprising acrystal of monohydrochloride of a compound represented by Formula (I):

wherein the crystal exhibits X-ray powder diffraction spectrum havingpeaks at diffraction angles 2θ: 8.0°±0.2°, 14.1°±0.2°, 20.6°±0.2°,21.0°±0.2°, and 25.8°±0.2°.
 2. A pharmaceutical composition comprising acrystal of monohydrochloride of a compound represented by Formula (I):

wherein the crystal exhibits X-ray powder diffraction spectrum havingpeaks at diffraction angles 2θ: 6.8°±0.2°, 8.0°±0.2°, 14.1°±0.2°,17.9°±0.2°, 18.5°±0.2°, 20.6°±0.2°, 21.0°±0.2°, 22.5°±0.2°, 25.8°±0.2°,and 28.4°±0.2°.
 3. A pharmaceutical composition comprising a crystal ofmonohydrochloride of a compound represented by Formula (I):

wherein the crystal exhibits X-ray powder diffraction spectrum havingpeaks at diffraction angles 2θ: 23.9°±0.2°, 25.9°±0.2°, 26.2°±0.2°,26.7°±0.2°, and 28.4°±0.2°.
 4. A pharmaceutical composition comprising acrystal of monohydrochloride of a compound represented by Formula al:

wherein the crystal exhibits X-ray powder diffraction spectrum havingpeaks at diffraction angles 2θ: 7.9°±0.2°, 9.7°±0.2°, 11.9°±0.2°,15.8°±0.2°, 18.5°±0.2°, 23.9°±0.2°, 25.9°±0.2°, 26.2°±0.2°, 26.7°±0.2°,and 28.4°±0.2°.
 5. A pharmaceutical composition comprising a crystal ofmonohydrochloride of a compound represented by Formula (I):

wherein the crystal exhibits X-ray powder diffraction spectrum havingpeaks at diffraction angles 2θ: 5.4°±0.2°, 16.3°±0.2°, 21.6°±0.2°,23.2°±0.2°, and 23.7°±0.2°.
 6. A pharmaceutical composition comprising acrystal of monohydrochloride of a compound represented by Formula (I):

wherein the crystal exhibits X-ray powder diffraction spectrum havingpeaks at diffraction angles 2θ: 5.4°±0.2°, 8.9°±0.2°, 11.7°±0.2°,13.8°±0.2°, 16.3°±0.2°, 20.9°±0.2°, 21.6°±0.2°, 23.2°±0.2°, 23.7°±0.2°,and 26.6°±0.2°.